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Sample records for asymptomatic brca2 mutation

  1. BRCA1 and BRCA2 Mutations

    MedlinePlus

    ... mutation. Should You Be Tested? If you answer “yes” to any of the following questions, genetic risk assessment is ... known BRCA1 or BRCA2 mutation? If you answer “yes” to any of the following questions, genetic risk assessment may ...

  2. BRCA1 and BRCA2 Mutations in African Americans

    DTIC Science & Technology

    2002-04-01

    genetic testing in African Americans must include the entire coding and flanking non-coding regions of the BRCA2 gene . "* It is noteworthy that BRCA ...Over 80% of inherited breast cancer is due to mutations in the breast cancer predisposing genes BRCA ] and BRCA2. In one of the largest studies of high...population 25-27,32. Therefore, genetic testing in African Americans must include complete sequencing of both BRCA 1 and BRCA2 genes . Familial cancer

  3. Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation.

    PubMed

    Vyas, Ojas; Leung, Keith; Ledbetter, Leslie; Kaley, Kristin; Rodriguez, Teresa; Garcon, Marie C; Saif, Muhammad W

    2015-02-01

    Patients with BRCA-1 and BRCA-2 germ line mutations are at an increased risk of developing pancreatic adenocarcinoma (PAC). In particular, the BRCA-2 mutation has been associated with a relative risk of developing PAC of 3.51. The BRCA-2 protein is involved in repair of double-stranded DNA breaks. Recent reports have suggested that in the setting of impaired DNA repair, chemotherapeutic agents that induce DNA damage, such as platinum-based antineoplastic drugs (platins) and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors), have improved efficacy. However, because of the relative rarity of BRCA-related PAC, studies evaluating such agents in this setting are scarce. Patients with a known BRCA-2 mutation and PAC were retrospectively reviewed. Ten patients with PAC and BRCA-2 mutation were identified. Four patients (40%) were of Ashkenazi Jewish descent. Seven patients (70%) received platinum agents, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Overall, chemotherapy was well tolerated with expected side effects. Patients with a BRCA-2 mutation and PAC represent a group with a unique biology underlying their cancer. Chemotherapies such as platinum derivatives, mitomycin-C, topoisomerase-I inhibitors, and PARP inhibitors targeting DNA require further investigation in this population. Genetic testing may guide therapy in the future.

  4. Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania.

    PubMed

    Janavičius, Ramūnas; Rudaitis, Vilius; Mickys, Ugnius; Elsakov, Pavel; Griškevičius, Laimonas

    2014-05-01

    There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1-3 deletion and BRCA2 c.658_659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5-0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene.

  5. Identification of a founder BRCA2 mutation in Sardinia

    PubMed Central

    Pisano, M; Cossu, A; Persico, I; Palmieri, G; Angius, A; Casu, G; Palomba, G; Sarobba, M G; Rocca, P C Ossu; Dedola, M F; Olmeo, N; Pasca, A; Budroni, M; Marras, V; Pisano, A; Farris, A; Massarelli, G; Pirastu, M; Tanda, Francesco

    2000-01-01

    Sardinian population can be instrumental in defining the molecular basis of cancer, using the identity-by-descent method. We selected seven Sardinian breast cancer families originating from the northern-central part of the island with multiple affected members in different generations. We genotyped 106 members of the seven families and 20 control nuclear families with markers flanking BRCA2 locus at 13q12–q13. The detection of a common haplotype shared by four out of seven families (60%) suggests the presence of a founder BRCA2 mutation. Direct sequencing of BRCA2 coding exons of patients carrying the shared haplotype, allowed the identification of a ‘frame-shift’ mutation at codon 2867 (8765delAG), causing a premature termination-codon. This mutation was found in breast cancer patients as well as one prostate and one bladder cancer patient with shared haplotype. We then investigated the frequency of 8765delAG in the Sardinian breast cancer population by analysing 270 paraffin-embedded normal tissue samples from breast cancer patients. Five patients (1.7%) were found to be positive for the 8765delAG mutation. Discovery of a founder mutation in Sardinia through the identity-by-descent method demonstrates that this approach can be applied successfully to find mutations either for breast cancer or for other types of tumours. © 2000 Cancer Research Campaign PMID:10682665

  6. Founder mutations in BRCA1 and BRCA2 genes.

    PubMed

    Ferla, R; Calò, V; Cascio, S; Rinaldi, G; Badalamenti, G; Carreca, I; Surmacz, E; Colucci, G; Bazan, V; Russo, A

    2007-06-01

    BRCA1 and BRCA2 germline mutations contribute to a significant number of familial and hereditary breast and/or ovarian cancers. The proportion of high-risk families with breast and/or ovarian cancer cases due to mutations in these tumor suppressor genes varies widely among populations. In some population, a wide spectrum of different mutations in both genes are present, whereas in other groups specific mutations in BRCA1 and BRCA2 have been reported with high frequency. Most of these mutations are prevalent in restricted populations as consequence of a founder effect. The comparison of haplotypes between families with the same mutation can distinguish whether high-frequency alleles derive from an older or more recent single mutational event or whether they have arisen independently more than once. Here, we review some of the most well-known and significant examples of founder mutations in BRCA genes found in European and non-European populations. In conclusion, the identification of the ethnic group of families undergoing genetic counseling enables the geneticist and oncologist to make more specific choices, leading to simplify the clinical approach to genetic testing carried out on members of high-risk families. Futhermore, the high frequency of founder mutations, allowing to analyze a large number of cases, might provide accurate information regarding their penetrance.

  7. Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors

    PubMed Central

    Decker, Brennan; Karyadi, Danielle M.; Davis, Brian W.; Karlins, Eric; Tillmans, Lori S.; Stanford, Janet L.; Thibodeau, Stephen N.; Ostrander, Elaine A.

    2016-01-01

    To identify clinically important molecular subtypes of prostate cancer (PCa), we characterized the somatic landscape of aggressive tumors via deep, whole-genome sequencing. In our discovery set of ten tumor/normal subject pairs with Gleason scores of 8–10 at diagnosis, coordinated analysis of germline and somatic variants, including single-nucleotide variants, indels, and structural variants, revealed biallelic BRCA2 disruptions in a subset of samples. Compared to the other samples, the PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature, featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for deletions, especially those longer than 10 bp. We next performed a BRCA2 deficiency-targeted reanalysis of 150 metastatic PCa tumors, and each of the 18 BRCA2-mutated samples recapitulated the BRCA2 deficiency-associated mutation signature, underscoring the potent influence of these lesions on somatic mutagenesis and tumor evolution. Among all 21 individuals with BRCA2-deficient tumors, only about half carried deleterious germline alleles. Importantly, the somatic mutation signature in tumors with one germline and one somatic risk allele was indistinguishable from those with purely somatic mutations. Our observations clearly demonstrate that BRCA2-disrupted tumors represent a unique and clinically relevant molecular subtype of aggressive PCa, highlighting both the promise and utility of this mutation signature as a prognostic and treatment-selection biomarker. Further, any test designed to leverage BRCA2 status as a biomarker for PCa must consider both germline and somatic mutations and all types of deleterious mutations. PMID:27087322

  8. Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families

    PubMed Central

    NOVAKOVIĆ, SRDJAN; MILATOVIĆ, MAŠA; CERKOVNIK, PETRA; STEGEL, VIDA; KRAJC, MATEJA; HOČEVAR, MARKO; ŽGAJNAR, JANEZ; VAKSELJ, ALEŠ

    2012-01-01

    The estimated proportion of hereditary breast and ovarian cancers among all breast and ovarian cancer cases is 5–10%. According to the literature, inherited mutations in the BRCA1 and BRCA2 tumour-suppressor genes, account for the majority of hereditary breast and ovarian cancer cases. The aim of this report is to present novel mutations that have not yet been described in the literature and pathogenic BRCA1 and BRCA2 mutations which have been detected in HBOC families for the first time in the last three years. In the period between January 2009 and December 2011, 559 individuals from 379 families affected with breast and/or ovarian cancer were screened for mutations in the BRCA1 and BRCA2 genes. Three novel mutations were detected: one in BRCA1 - c.1193C>A (p.Ser398*) and two in BRCA2 - c.5101C>T (p.Gln1701*) and c.5433_5436delGGAA (p.Glu1811Aspfs*3). These novel mutations are located in the exons 11 of BRCA1 or BRCA2 and encode truncated proteins. Two of them are nonsense while one is a frameshift mutation. Also, 11 previously known pathogenic mutations were detected for the first time in the HBOC families studied here (three in BRCA1 and eight in BRCA2). All, except one cause premature formation of stop codons leading to truncation of the respective BRCA1 or BRCA2 proteins. PMID:22923021

  9. The spectrum of BRCA1 and BRCA2 mutations in breast cancer patients in the Bahamas.

    PubMed

    Akbari, M R; Donenberg, T; Lunn, J; Curling, D; Turnquest, T; Krill-Jackson, E; Zhang, S; Narod, S A; Hurley, J

    2014-01-01

    We sought to identify the full range of founder mutations in BRCA1 and BRCA2 in the Bahamas and to estimate the proportion of all BRCA1 and BRCA2 mutations that are accounted for by founder mutations. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history. A founder mutation had previously been identified in 49 patients. We conducted full sequencing of the BRCA1 and BRCA2 genes and multiplex ligation-dependent probe amplification (MLPA) for 156 patients. A novel founder mutation in BRCA2 (exon 17 818delA) was seen in four different patients and five other unique mutations in BRCA1 and BRCA2, including a large deletion (exons 8-9) in BRCA1. In total, a mutation was seen in 58 of the 214 patients (27%); 92% of carriers carried one of the seven founder mutations. Approximately 27% of unselected cases of breast cancer in the Bahamian population are attributable to a mutation in BRCA1 or BRCA2, a prevalence which far exceeds that of any other country. The majority of women who carry a mutation in the Bahamas, carry one of the seven founder mutations, making it possible to offer genetic testing to all women at risk for breast cancer in the Bahamas.

  10. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries

    PubMed Central

    Kwong, Ava; Shin, Vivian Y; Ho, John C W; Kang, Eunyoung; Nakamura, Seigo; Teo, Soo-Hwang; Lee, Ann S G; Sng, Jen-Hwei; Ginsburg, Ophira M; Kurian, Allison W; Weitzel, Jeffrey N; Siu, Man-Ting; Law, Fian B F; Chan, Tsun-Leung; Narod, Steven A; Ford, James M; Ma, Edmond S K; Kim, Sung-Won

    2015-01-01

    Approximately 5%–10% of breast cancers are due to genetic predisposition caused by germline mutations; the most commonly tested genes are BRCA1 and BRCA2 mutations. Some mutations are unique to one family and others are recurrent; the spectrum of BRCA1/BRCA2 mutations varies depending on the geographical origins, populations or ethnic groups. In this review, we compiled data from 11 participating Asian countries (Bangladesh, Mainland China, Hong Kong SAR, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Thailand and Vietnam), and from ethnic Asians residing in Canada and the USA. We have additionally conducted a literature review to include other Asian countries mainly in Central and Western Asia. We present the current pathogenic mutation spectrum of BRCA1/BRCA2 genes in patients with breast cancer in various Asian populations. Understanding BRCA1/BRCA2 mutations in Asians will help provide better risk assessment and clinical management of breast cancer. PMID:26187060

  11. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries.

    PubMed

    Kwong, Ava; Shin, Vivian Y; Ho, John C W; Kang, Eunyoung; Nakamura, Seigo; Teo, Soo-Hwang; Lee, Ann S G; Sng, Jen-Hwei; Ginsburg, Ophira M; Kurian, Allison W; Weitzel, Jeffrey N; Siu, Man-Ting; Law, Fian B F; Chan, Tsun-Leung; Narod, Steven A; Ford, James M; Ma, Edmond S K; Kim, Sung-Won

    2016-01-01

    Approximately 5%-10% of breast cancers are due to genetic predisposition caused by germline mutations; the most commonly tested genes are BRCA1 and BRCA2 mutations. Some mutations are unique to one family and others are recurrent; the spectrum of BRCA1/BRCA2 mutations varies depending on the geographical origins, populations or ethnic groups. In this review, we compiled data from 11 participating Asian countries (Bangladesh, Mainland China, Hong Kong SAR, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Thailand and Vietnam), and from ethnic Asians residing in Canada and the USA. We have additionally conducted a literature review to include other Asian countries mainly in Central and Western Asia. We present the current pathogenic mutation spectrum of BRCA1/BRCA2 genes in patients with breast cancer in various Asian populations. Understanding BRCA1/BRCA2 mutations in Asians will help provide better risk assessment and clinical management of breast cancer.

  12. Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

    PubMed Central

    Steinmann, D; Bremer, M; Rades, D; Skawran, B; Siebrands, C; Karstens, J H; Dörk, T

    2001-01-01

    Mutations of the BRCA1 or BRCA2 genes have been shown to strongly predispose towards the development of contralateral breast cancer in patients from large multi-case families. In order to test the hypothesis that BRCA1 and BRCA2 mutations are more frequent in patients with bilateral breast cancer, we have investigated a hospital-based series of 75 consecutive patients with bilateral breast cancer and a comparison group of 75 patients with unilateral breast cancer, pairwise matched by age and family history, for mutations in the BRCA1 and BRCA2 genes. Five frameshift deletions (517delGT in BRCA1; 4772delA, 5946delCT, 6174delT and 8138del5 in BRCA2) were identified in patients with bilateral disease. No further mutations, apart from polymorphisms and 3 rare unclassified variants, were found after scanning the whole BRCA1 and BRCA2 coding sequence. Three pathogenic BRCA1 mutations (Cys61Gly, 3814del5, 5382insC) were identified in the group of patients with unilateral breast cancer. The frequencies of common BRCA1 and BRCA2 missense variants were not different between the 2 groups. In summary, we did not find a significantly increased prevalence of BRCA1 and BRCA2 mutations in a hospital-based cohort of German patients with bilateral breast cancer. We conclude that bilaterality of breast cancer on its own is not strongly associated with BRCA1 and BRCA2 mutations when adjusted for age and family history. The high frequency of bilateral disease in multi-case breast cancer families may be due to a familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 and BRCA2 mutations. © 2001 Cancer Research Campaignhttp://www.bjcancer.com PMID:11556836

  13. Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer.

    PubMed

    Steinmann, D; Bremer, M; Rades, D; Skawran, B; Siebrands, C; Karstens, J H; Dörk, T

    2001-09-14

    Mutations of the BRCA1 or BRCA2 genes have been shown to strongly predispose towards the development of contralateral breast cancer in patients from large multi-case families. In order to test the hypothesis that BRCA1 and BRCA2 mutations are more frequent in patients with bilateral breast cancer, we have investigated a hospital-based series of 75 consecutive patients with bilateral breast cancer and a comparison group of 75 patients with unilateral breast cancer, pairwise matched by age and family history, for mutations in the BRCA1 and BRCA2 genes. Five frameshift deletions (517delGT in BRCA1; 4772delA, 5946delCT, 6174delT and 8138del5 in BRCA2) were identified in patients with bilateral disease. No further mutations, apart from polymorphisms and 3 rare unclassified variants, were found after scanning the whole BRCA1 and BRCA2 coding sequence. Three pathogenic BRCA1 mutations (Cys61Gly, 3814del5, 5382insC) were identified in the group of patients with unilateral breast cancer. The frequencies of common BRCA1 and BRCA2 missense variants were not different between the 2 groups. In summary, we did not find a significantly increased prevalence of BRCA1 and BRCA2 mutations in a hospital-based cohort of German patients with bilateral breast cancer. We conclude that bilaterality of breast cancer on its own is not strongly associated with BRCA1 and BRCA2 mutations when adjusted for age and family history. The high frequency of bilateral disease in multi-case breast cancer families may be due to a familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 and BRCA2 mutations.

  14. Aurora A is a prognostic marker for breast cancer arising in BRCA2 mutation carriers.

    PubMed

    Aradottir, Margret; Reynisdottir, Sigridur T; Stefansson, Olafur A; Jonasson, Jon G; Sverrisdottir, Asgerdur; Tryggvadottir, Laufey; Eyfjord, Jorunn E; Bodvarsdottir, Sigridur K

    2015-01-01

    Overexpression of the Aurora A kinase has been shown to have prognostic value in breast cancer. Previously, we showed a significant association between AURKA gene amplification and BRCA2 mutation in breast cancer. The aim of this study was to assess the prognostic impact of Aurora A overexpression on breast cancer arising in BRCA2 mutation carriers. Aurora A expression was evaluated by immunohistochemistry on breast tumour tissue microarrays from 107 BRCA2 999del5 mutation carriers and 284 of sporadic origin. Prognostic value of Aurora A nuclear staining was estimated in relation to clinical markers and adjuvant treatment, using multivariate Cox's proportional hazards ratio regression model. BRCA2 wild-type allele loss was measured by TaqMan in BRCA2 mutated tumour samples. All statistical tests were two sided. Multivariate analysis of breast cancer-specific survival, including proliferative markers and treatment, indicated independent prognostic value of Aurora A nuclear staining for BRCA2 mutation carriers (hazards ratio = 7.06; 95% confidence interval = 1.23-40.6; p = 0.028). Poor breast cancer-specific survival of BRCA2 mutation carriers was found to be significantly associated with combined Aurora A nuclear expression and BRCA2 wild type allele loss in tumours (p < 0.001). Multivariate analysis indicated independent prognostic value of both positive Aurora A nuclear staining (hazards ratio = 10.09; 95% confidence interval = 1.19-85.4, p = 0.034) and BRCA2 wild type allele loss (hazards ratio = 9.63; 95% confidence interval = 1.81-51.0, p = 0.008) for BRCA2 mutation carriers. Aurora A nuclear expression was found to be a significant prognostic marker for BRCA2 mutation carriers, independent of clinical parameters and adjuvant treatment. Our conclusion is that treatment benefits for BRCA2 mutation carriers and sporadic breast cancer patients with Aurora A positive tumours may be enhanced by giving attention to Aurora A

  15. A brother and sister with breast cancer, BRCA2 mutations and bilateral supernumerary nipples

    PubMed Central

    Coad, Ryan

    2017-01-01

    We describe a 54-year-old man with breast cancer and a BRCA2 mutation who was also found to have bilateral supernumerary nipples. His sister, also with a BRCA2 mutation, was diagnosed with breast cancer in her late forties; she also had bilateral supernumerary nipples. We address the significance of breast cancer arising in breast tissue underlying supernumerary nipples; the known association between supernumerary nipples and genitourinary malignancies/malformations and the possible link between BRCA2 and supernumerary nipple development. We believe that this is the first described case of the latter. We then outline an approach to further management for supernumerary nipple cases. PMID:28361071

  16. Women with BRCA1 and BRCA2 mutations survive ovarian cancer at higher rates

    Cancer.gov

    Results from a National Cancer Institute (NCI) sponsored multicenter study published in the Journal of the American Medical Association on January 25, 2012, provides strong evidence that BRCA1 and BRCA2 gene mutation carriers with ovarian cancer were more

  17. Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

    PubMed Central

    Taylor, Renea A.; Fraser, Michael; Livingstone, Julie; Espiritu, Shadrielle Melijah G.; Thorne, Heather; Huang, Vincent; Lo, Winnie; Shiah, Yu-Jia; Yamaguchi, Takafumi N.; Sliwinski, Ania; Horsburgh, Sheri; Meng, Alice; Heisler, Lawrence E.; Yu, Nancy; Yousif, Fouad; Papargiris, Melissa; Lawrence, Mitchell G.; Timms, Lee; Murphy, Declan G.; Frydenberg, Mark; Hopkins, Julia F.; Bolton, Damien; Clouston, David; McPherson, John D.; van der Kwast, Theodorus; Boutros, Paul C.; Risbridger, Gail P.; Bristow, Robert G.

    2017-01-01

    Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment. PMID:28067867

  18. Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.

    PubMed

    Taylor, Renea A; Fraser, Michael; Livingstone, Julie; Espiritu, Shadrielle Melijah G; Thorne, Heather; Huang, Vincent; Lo, Winnie; Shiah, Yu-Jia; Yamaguchi, Takafumi N; Sliwinski, Ania; Horsburgh, Sheri; Meng, Alice; Heisler, Lawrence E; Yu, Nancy; Yousif, Fouad; Papargiris, Melissa; Lawrence, Mitchell G; Timms, Lee; Murphy, Declan G; Frydenberg, Mark; Hopkins, Julia F; Bolton, Damien; Clouston, David; McPherson, John D; van der Kwast, Theodorus; Boutros, Paul C; Risbridger, Gail P; Bristow, Robert G

    2017-01-09

    Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.

  19. Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers

    PubMed Central

    2010-01-01

    Introduction Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. Methods We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Results SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r2 = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, Ptrend = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, Ptrend = 0.018). Conclusions This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations. PMID:21114847

  20. First case report of an adrenocortical carcinoma caused by a BRCA2 mutation

    PubMed Central

    El Ghorayeb, Nada; Grunenwald, Solange; Nolet, Serge; Primeau, Vanessa; Côté, Stéphanie; Maugard, Christine M.; Lacroix, André; Gaboury, Louis; Bourdeau, Isabelle

    2016-01-01

    Abstract Background: Adrenocortical carcinoma (ACC) may rarely be a component of inherited cancer syndromes such as Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome. ACC caused by a BRCA2 mutation has never been reported. Methods: Nucleotide sequencing of BRCA2 in lymphocyte and tumoral DNA of a 50-year-old male who presented with an androgen-secreting ACC and a strong family history of breast, ovarian, and pancreatic cancers. Results: A germline BRCA2 2 bp heterozygous deletion at nucleotide 8765 (8765delAG) leading to a frameshift mutation (p.Glu2846GlyfsX23) was detected. Only the BRCA2 deleted allele was retained in the ACC tumoral DNA compared with the control DNA supporting a loss of heterozygosity in the tumor. Conclusion: This is the first reported case of a patient with ACC associated with a BRCA2 germline mutation. Loss of heterozygosity in ACC DNA suggests a causal link with the BRCA2 8765delAG mutation. PMID:27603373

  1. Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families.

    PubMed Central

    Tonin, P N; Mes-Masson, A M; Futreal, P A; Morgan, K; Mahon, M; Foulkes, W D; Cole, D E; Provencher, D; Ghadirian, P; Narod, S A

    1998-01-01

    We have identified four mutations in each of the breast cancer-susceptibility genes, BRCA1 and BRCA2, in French Canadian breast cancer and breast/ovarian cancer families from Quebec. To identify founder effects, we examined independently ascertained French Canadian cancer families for the distribution of these eight mutations. Mutations were found in 41 of 97 families. Six of eight mutations were observed at least twice. The BRCA1 C4446T mutation was the most common mutation found, followed by the BRCA2 8765delAG mutation. Together, these mutations were found in 28 of 41 families identified to have a mutation. The odds of detection of any of the four BRCA1 mutations was 18.7x greater if one or more cases of ovarian cancer were also present in the family. The odds of detection of any of the four BRCA2 mutations was 5.3x greater if there were at least five cases of breast cancer in the family. Interestingly, the presence of a breast cancer case <36 years of age was strongly predictive of the presence of any of the eight mutations screened. Carriers of the same mutation, from different families, shared similar haplotypes, indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population. The identification of common BRCA1 and BRCA2 mutations will facilitate carrier detection in French Canadian breast cancer and breast/ovarian cancer families. PMID:9792861

  2. Recurrent BRCA1 and BRCA2 mutations in Mexican women with breast cancer

    PubMed Central

    Torres-Mejía, Gabriela; Royer, Robert; Llacuachaqui, Marcia; Akbari, Mohammad R.; Giuliano, Anna R.; Martínez-Matsushita, Louis; Angeles-Llerenas, Angélica; Ortega-Olvera, Carolina; Ziv, Elad; Lazcano-Ponce, Eduardo; Phelan, Catherine M.; Narod, Steven A.

    2015-01-01

    Background Germline mutations in the BRCA1 and BRCA2 genes confer an estimated 58–80% lifetime risk of breast cancer. In general, screening is done for cancer patients if a relative has been diagnosed with breast or ovarian cancer. There are few data on the prevalence of mutations in these genes in Mexican women with breast cancer and this hampers efforts to develop screening policies in Mexico. Methods We screened 810 unselected women with breast cancer from three cities in Mexico (Mexico City, Veracruz and Monterrey) for mutations in BRCA1 and BRCA2, including a panel of 26 previously reported mutations. Results Thirty-five mutations were identified in 34 women (4.3% of total) including 20 BRCA1 mutations and 15 BRCA2 mutations. Twenty-two of the 35 mutations were recurrent mutations (62.8%). Only five of the 34 mutation carriers had a first-degree relative with breast cancer (three with BRCA1 and two with BRCA2 mutations). Conclusion These results support the rationale for a strategy of screening for recurrent mutations in all women with breast cancer in Mexico, as opposed to restricting screening to those with a sister or mother with breast or ovarian cancer. Impact These results will impact cancer genetic testing in Mexico and the identification of at-risk individuals who will benefit from increased surveillance. PMID:25371446

  3. BRCA1 and BRCA2 mutations in breast cancer patients from Venezuela.

    PubMed

    Lara, Karlena; Consigliere, Nigmet; Pérez, Jorge; Porco, Antonietta

    2012-01-01

    A sample of 58 familial breast cancer patients from Venezuela were screened for germline mutations in the coding sequences and exon-intron boundaries of BRCA1 (MIM no. 113705) and BRCA2 (MIM no. 600185) genes by using conformation-sensitive gel electrophoresis. Ashkenazi Jewish founder mutations were not found in any of the samples. We identified 6 (10.3%) and 4 (6.9%) patients carrying germline mutations in BRCA1 and BRCA2, respectively. Four pathogenic mutations were found in BRCA1, one is a novel mutation (c.951_952insA), while the other three had been previously reported (c.1129_1135insA, c.4603G>T and IVS20+1G>A). We also found 4 pathogenic mutations in BRCA2, two novel mutations (c.2732_2733insA and c.3870_3873delG) and two that have been already reported (c.3036_3039delACAA and c.6024_6025_delTA). In addition, 17 variants of unknown significance (6 BRCA1 variants and 11 BRCA2 variants), 5 BRCA2 variants with no clinical importance and 22 polymorphisms (12 in BRCA1 and 10 in BRCA2) were also identified. This is the first genetic study on BRCA gene mutations conducted in breast cancer patients from Venezuela. The ethnicity of our population, as well as the heterogeneous and broad spectrum of BRCA genes mutations, must be considered to optimize genetic counseling and disease prevention in affected families.

  4. A Comprehensive Focus on Global Spectrum of BRCA1 and BRCA2 Mutations in Breast Cancer

    PubMed Central

    Karami, Fatemeh; Mehdipour, Parvin

    2013-01-01

    Breast cancer (BC) is the most common cancer of women all over the world. BRCA1 and BRCA2 gene mutations comprise the most important genetic susceptibility of BC. Except for few common mutations, the spectrum of BRCA1 and BRCA2 mutations is heterogeneous in diverse populations. 185AGdel and 5382insC are the most important BRCA1 and BRCA2 alterations which have been encountered in most of the populations. After those Ashkenazi founder mutations, 300T>G also demonstrated sparse frequency in African American and European populations. This review affords quick access to the most frequent alterations among various populations which could be helpful in BRCA screening programs. PMID:24312913

  5. BRCA1 and BRCA2 mutations and the risk for colorectal cancer.

    PubMed

    Sopik, V; Phelan, C; Cybulski, C; Narod, S A

    2015-05-01

    Women who carry a BRCA1 or BRCA2 mutation are at high risk of breast and ovarian cancer, and may be at moderately increased risk of other cancer types. This review examines studies to date that have evaluated the risk of BRCA1 and BRCA2 mutations for colorectal cancer. Accurate knowledge of colorectal cancer risk in BRCA1/2 carriers is important, because colonoscopy screening can prevent colorectal cancer through the removal of adenomatous polyps. Most studies that have identified an increased risk for colorectal cancer in BRCA1/2 mutation carriers were in high-risk cancer families, while studies that found no association were conducted in specific populations and involved the analysis of founder mutations. A recent prospective study of 7015 women with a BRCA1 or BRCA2 mutation identified significant fivefold increased risk of colorectal cancer among BRCA1 mutation carriers younger than 50 years [standardized incidence ratio (SIR): 4.8; 95% CI: 2.2-9], but not in women with a BRCA2 mutation or in older women. Based on this evidence, women with BRCA1 mutations should be counseled about their increased risk for early-onset colorectal cancer, and offered colonoscopy at 3- to 5-year intervals between the ages of 40 and 50 years, and should follow population guidelines thereafter.

  6. The Role of BRCA2 Mutation Status as Diagnostic, Predictive, and Prognosis Biomarker for Pancreatic Cancer

    PubMed Central

    Garcia-Foncillas, Jesus

    2016-01-01

    Pancreatic cancer is one of the deadliest cancers worldwide, and life expectancy after diagnosis is often short. Most pancreatic tumours appear sporadically and have been highly related to habits such as cigarette smoking, high alcohol intake, high carbohydrate, and sugar consumption. Other observational studies have suggested the association between pancreatic cancer and exposure to arsenic, lead, or cadmium. Aside from these factors, chronic pancreatitis and diabetes have also come to be considered as risk factors for these kinds of tumours. Studies have found that 10% of pancreatic cancer cases arise from an inherited syndrome related to some genetic alterations. One of these alterations includes mutation in BRCA2 gene. BRCA2 mutations impair DNA damage response and homologous recombination by direct regulation of RAD51. In light of these findings that link genetic factors to tumour development, DNA damage agents have been proposed as target therapies for pancreatic cancer patients carrying BRCA2 mutations. Some of these drugs include platinum-based agents and PARP inhibitors. However, the acquired resistance to PARP inhibitors has created a need for new chemotherapeutic strategies to target BRCA2. The present systematic review collects and analyses the role of BRCA2 alterations to be used in early diagnosis of an inherited syndrome associated with familiar cancer and as a prognostic and predictive biomarker for the management of pancreatic cancer patients. PMID:28078281

  7. BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland.

    PubMed

    Perkowska, Magdalena; BroZek, Izabela; Wysocka, Barbara; Haraldsson, Karin; Sandberg, Therese; Johansson, Ulla; Sellberg, Gunilla; Borg, Ake; Limon, Janusz

    2003-05-01

    Sixty high-risk breast and/or ovarian cancer families from North-Eastern Poland were screened for germline mutations in BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185), using a combination of protein truncation test, denaturing high-performance liquid chromatography and direct sequencing. Sixteen (27%) of the families were found to carry nine different BRCA mutations, including 14 families with BRCA1 mutation and two families with BRCA2 mutation. The results suggest the presence of two strong BRCA1 founder mutations in the Polish population - 5382insC (6 families) and 300T>G (Cys61Gly; 3 families). The remaining seven mutations were found in single families and included three previously reported BRCA1 mutations (185delAG, 2682C>T [Gln855Ter] and 3819del5), a novel BRCA1 mutation (IVS14+1G>A), as well as two BRCA2 mutations (4088delA and 7985G>A [Trp2586Ter]) not previously observed in Polish families. We confirm the strong influence of two Central-Eastern European BRCA1 founder mutations in familial breast and/or ovarian cancer in Poland. We also conclude that the Polish population has a more dispersed BRCA mutation spectrum than had been earlier thought. This warrants further careful BRCA mutation screening in order to optimise genetic counselling and disease prevention in affected families.

  8. Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population

    SciTech Connect

    Friedman, L.S.; Gayther, S.A.; Ponder, B.A.J.

    1997-02-01

    A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene. 23 refs., 1 fig., 5 tabs.

  9. Detection of BRCA1 and BRCA2 germline mutations in Japanese population using next-generation sequencing

    PubMed Central

    Hirotsu, Yosuke; Nakagomi, Hiroshi; Sakamoto, Ikuko; Amemiya, Kenji; Mochizuki, Hitoshi; Omata, Masao

    2015-01-01

    Tumor suppressor genes BRCA1 and BRCA2 are the two main breast and ovarian cancer susceptibility genes, and their genetic testing has been used to evaluate the risk of hereditary breast and ovarian cancer (HBOC). While several studies have reported the prevalence of BRCA1 and BRCA2 mutations in Japanese populations, there is insufficient information about deleterious mutations compared with western countries. Moreover, because many rare variants are found in BRCA1 and BRCA2, both of which encode large proteins, it is difficult to sequence all coding regions using the Sanger method for mutation detection. In this study, therefore, we performed next-generation sequencing (NGS) analysis of the entire coding regions of BRCA1 and BRCA2 in 135 breast and/or ovarian cancer patients. Deleterious BRCA1 and BRCA2 mutations were detected in 10 patients (7.4%) by NGS analysis. Of these, one mutation in BRCA1 and two in BRCA2 had not been reported previously. Furthermore, a BRCA2 mutation found in a proband was also identified in two unaffected relatives. These data suggest the utility of screening BRCA1 and BRCA2 mutations by NGS in clinical diagnosis. PMID:25802882

  10. Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel.

    PubMed

    Laitman, Yael; Simeonov, Monica; Herskovitz, Liron; Kushnir, Anya; Shimon-Paluch, Shani; Kaufman, Bella; Zidan, Jamal; Friedman, Eitan

    2012-06-01

    The spectrum of germline mutations among Jewish non Ashkenazi high risk breast/ovarian cancer families includes a few predominant mutations in BRCA1 (185delAG and Tyr978X) and BRCA2 (8765delAG). A few additional recurring mutations [A1708E, 981delAT, C61G (BRCA1) R2336P, and IVS2 + 1G > A (BRCA2)] have been reported in Jewish non Ashkenazi families. The 4153delA*BRCA1 C61G*BRCA1 and the 4075delGT*BRCA2 has been reported to recur in Russian/Polish non Jews and Ashkenazim, respectively. The rate of these recurring mutations has not been reported in Israeli high risk families. Genotyping for these recurring mutations by restriction enzyme digest and sequencing method was applied to high risk, predominantly cancer affected, unrelated Israeli individuals of Ashkenazi (n = 827), non Ashkenazi (n = 2,777), non Jewish Caucasians (n = 193), and 395 of mixed ethnicity. Jewish participants included 827 Ashkenazi, 804 Balkans, 847 North Africans, 234 Yemenites, and 892 Asians (Iraq and Iran). Age at diagnosis of breast cancer (median ± SD) (n = 2,484) was 47.2 ± 9.6 for all women participants. Males (n = 236) were also included, of whom 24 had breast cancer and 35 had pancreatic cancer. Overall, 8/282 (2.8%) of the Balkan cases carried the BRCA1*A1708E mutation, 4/180 (2.2%) the R2336P mutation, and 0/270 the IVS2 + 1G > A BRCA2 mutations, respectively. Of North Africans, 7/264 (2.65%) carried the BRCA1*981delAT mutation. The BRCA1*C61G mutation was detected in 3/269 Ashkenazi, non Ashkenazi, and non Jewish Russians; the BRCA1*Tyr978X mutation was detected in 23/3220 individuals of non Ashkenazi origin, exclusively of Asian ethnicity (23/892, 2.6% of the Asians tested). The BRCA1*4153delA mutation was noted in 2/285 non Jewish Caucasians, and none of the Ashkenazim (n = 500) carried the BRCA2*4075delGT mutation. Jewish high risk families of North African, Asian, and Balkan descent should be screened for the 981delAT, Tyr978X, A1708E BRCA1, and the R2336P BRCA2 mutations

  11. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers.

    PubMed

    Thompson, D; Easton, D

    2001-02-01

    Cancer occurrence in 164 families with breast/ovarian cancer and germline BRCA2 mutations was studied to evaluate the evidence for genotype-phenotype correlations. Mutations in a central portion of the gene (the "ovarian cancer cluster region" [OCCR]) were associated with a significantly higher ratio of cases of ovarian:breast cancer in female carriers than were mutations 5' or 3' of this region (P<.0001), extending previous observations. The optimal definition of the OCCR, as judged on the basis of deviance statistics, was bounded by nucleotides 3059-4075 and 6503-6629. The relative and absolute risks of breast and ovarian cancer associated with OCCR and non-OCCR mutations were estimated by a conditional likelihood approach, conditioning on the set of mutations observed in the families. OCCR mutations were associated both with a highly significantly lower risk of breast cancer (relative risk [RR] 0.63; 95% confidence interval (95% CI) 0.46-0.84; P=.0012) and with a significantly higher risk of ovarian cancer (RR = 1.88; 95% CI = 1.08-3.33; P=.026). No other differences in breast or ovarian cancer risk, by mutation position, were apparent. There was some evidence for a lower risk of prostate cancer in carriers of an OCCR mutation (RR = 0.52; 95% CI = 0.24-1.00; P=.05), but there was no evidence of a difference in breast cancer risk in males. By age 80 years, the cumulative risk of breast cancer in male carriers of a BRCA2 mutation was estimated as 6.92% (95% CI = 1.20%-38.57%). Possible mechanisms for the variation in cancer risk are suggested by the coincidence of the OCCR with the RAD51-binding domain.

  12. Prevalence of BRCA1 and BRCA2 Jewish mutations in Spanish breast cancer patients

    PubMed Central

    Díez, O; Osorio, A; Robledo, M; Barroso, A; Domènech, M; Cortés, J; Albertos, J; Sanz, J; Brunet, J; SanRoḿn, J M; Alonso, M C; Baiget, M; Benítez, J

    1999-01-01

    We screened the 185delAG and 5382insC (BRCA1) and the 6174delT (BRCA2) mutation in 298 Spanish women with breast cancer. Two women (one with Sephardic ancestors) presented the 185delAG mutation and the same haplotype reported in Ashkenazim with this mutation. This suggests a common origin of the 185delAG in both Sephardic and Ashkenazi populations. © 1999 Cancer Research Campaign PMID:10098775

  13. Breast cancer risk in Chinese women with BRCA1 or BRCA2 mutations.

    PubMed

    Yao, Lu; Sun, Jie; Zhang, Juan; He, Yingjian; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

    2016-04-01

    BRCA1/2 mutations represent approximately 5 % of unselected Chinese women with breast cancer. However, the breast cancer risk of Chinese women with BRCA1/2 mutations is unknown. Therefore, the aim of this study was to estimate the age-specific cumulative risk of breast cancer in Chinese women who carry a BRCA1 or BRCA2 mutation. Our study included 1816 unselected Chinese women with breast cancer and 5549 female first-degree relatives of these probands. All probands were screened for BRCA1/2 mutation. The age-specific cumulative risks of BRCA1/2 carriers were estimated using the kin-cohort study by comparing the history of breast cancer in first-degree female relatives of BRCA1/2 carriers and non-carriers. Among the 1816 probands, 125 BRCA1/2 pathogenic mutations were identified (70 in the BRCA1 gene and 55 in the BRCA2 gene). The incidence of breast cancer in the first-degree female relatives of BRCA1/2 mutation carriers was significantly higher (3.7-fold and 4.4-fold for BRCA1 and BRCA2 mutation carriers, respectively) than in non-carriers. The estimated cumulative risks of breast cancer by age 70 years were 37.9 % [95 % confidence interval (CI) 24.1-54.4 %] for BRCA1 mutation carriers and 36.5 % (95 % CI 26.7-51.8 %) for BRCA2 mutation carriers, respectively. Our study suggests that the breast cancer risk of Chinese women with BRCA1/2 mutations appears to be relatively high by the age of 70. Therefore, genetic counseling, enhanced surveillance, and individual preventive strategies should be provided for Chinese women who carry a BRCA1/2 mutation.

  14. Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Phillips, Kelly-Anne; Milne, Roger L.; Rookus, Matti A.; Daly, Mary B.; Antoniou, Antonis C.; Peock, Susan; Frost, Debra; Easton, Douglas F.; Ellis, Steve; Friedlander, Michael L.; Buys, Saundra S.; Andrieu, Nadine; Noguès, Catherine; Stoppa-Lyonnet, Dominique; Bonadona, Valérie; Pujol, Pascal; McLachlan, Sue Anne; John, Esther M.; Hooning, Maartje J.; Seynaeve, Caroline; Tollenaar, Rob A.E.M.; Goldgar, David E.; Beth Terry, Mary; Caldes, Trinidad; Weideman, Prue C.; Andrulis, Irene L.; Singer, Christian F.; Birch, Kate; Simard, Jacques; Southey, Melissa C.; Olsson, Håkan L.; Jakubowska, Anna; Olah, Edith; Gerdes, Anne-Marie; Foretova, Lenka; Hopper, John L.

    2013-01-01

    Purpose To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Methods Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up. Results Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases). Conclusion This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses. PMID:23918944

  15. Robust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation

    PubMed Central

    Kass, Elizabeth M.; Lim, Pei Xin; Helgadottir, Hildur R.; Moynahan, Mary Ellen; Jasin, Maria

    2016-01-01

    The mammary gland undergoes significant proliferative stages after birth, but little is known about how the developmental changes impact DNA double-strand break (DSB) repair. Mutations in multiple genes involved in homology-directed repair (HDR), considered a particularly accurate pathway for repairing DSBs, are linked to breast cancer susceptibility, including BRCA2. Using reporter mice that express an inducible endonuclease, we find that HDR is particularly robust in mammary tissue during puberty and pregnancy, accounting for 34–40% of detected repair events, more than in other tissues examined. Brca2 hypomorphic mutation leads to HDR defects in mammary epithelium during puberty and pregnancy, including in different epithelial lineages. Notably, a similar dependence on Brca2 is observed in other proliferative tissues, including small intestine epithelium. Our results suggest that the greater reliance on HDR in the proliferating mammary gland, rather than a specific dependence on BRCA2, may increase its susceptibility to tumorigenesis incurred by BRCA2 mutation. PMID:27779185

  16. Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Peru

    PubMed Central

    Abugattas, Julio; Llacuachaqui, Marcia; Allende, Yasser Sullcahuaman; Velásquez, Abelardo Arias; Velarde, Raúl; Cotrina, José; Garcés, Milko; León, Mauricio; Calderón, Gabriela; de la Cruz, Miguel; Mora, Pamela; Royer, Robert; Herzog, Josef; Weitzel, Jeffrey N; Narod, Steven A

    2014-01-01

    The prevalence of BRCA1 and BRCA2 mutations among breast cancer patients in Peru has not yet been explored. We enrolled 266 women with breast cancer from a National cancer hospital in Lima, Peru, unselected for age or family history. DNA was screened with a panel of 114 recurrent Hispanic BRCA mutations (HISPANEL). Among the 266 cases, thirteen deleterious mutations were identified (eleven in BRCA1 and two in BRCA2), representing 5% of the total. The average age of breast cancer in the mutation-positive cases was 44 years. BRCA1 185delAG represented seven of the eleven mutations in BRCA1. Other mutations detected in BRCA1 included: two 2080delA, one 943ins10, and one 3878delTA. The BRCA2 3036del4 mutation was seen in two patients. Given the relatively low cost of the HISPANEL test, one should consider offering this test to all Peruvian women with breast or ovarian cancer. PMID:25256238

  17. Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Peru.

    PubMed

    Abugattas, J; Llacuachaqui, M; Allende, Y Sullcahuaman; Velásquez, A Arias; Velarde, R; Cotrina, J; Garcés, M; León, M; Calderón, G; de la Cruz, M; Mora, P; Royer, R; Herzog, J; Weitzel, J N; Narod, S A

    2015-10-01

    The prevalence of BRCA1 and BRCA2 mutations among breast cancer patients in Peru has not yet been explored. We enrolled 266 women with breast cancer from a National cancer hospital in Lima, Peru, unselected for age or family history. DNA was screened with a panel of 114 recurrent Hispanic BRCA mutations (HISPANEL). Among the 266 cases, 13 deleterious mutations were identified (11 in BRCA1 and 2 in BRCA2), representing 5% of the total. The average age of breast cancer in the mutation-positive cases was 44 years. BRCA1 185delAG represented 7 of 11 mutations in BRCA1. Other mutations detected in BRCA1 included: two 2080delA, one 943ins10, and one 3878delTA. The BRCA2 3036del4 mutation was seen in two patients. Given the relatively low cost of the HISPANEL test, one should consider offering this test to all Peruvian women with breast or ovarian cancer.

  18. Predictive Factors for BRCA1/BRCA2 Mutations in Women With Ductal Carcinoma In Situ

    PubMed Central

    Bayraktar, Soley; Elsayegh, Nisreen; Gutierrez Barrera, Angelica M.; Lin, Heather; Kuerer, Henry; Tasbas, Tunc; Muse, Kimberly I.; Ready, Kaylene; Litton, Jennifer; Meric-Bernstam, Funda; Hortobagyi, Gabriel N.; Albarracin, Constance T.; Arun, Banu

    2015-01-01

    Background It is unclear whether women with ductal carcinoma in situ (DCIS), like their counterparts with invasive breast cancer, warrant genetic risk assessment and testing on the basis of high-risk variables. The authors of this report identified predictive factors for mutations in the breast cancer-susceptibility genes BRCA1 and BRCA2 in women who were diagnosed with DCIS. Methods One hundred eighteen women with DCIS who were referred for genetic counseling and underwent genetic testing for BRCA1/BRCA2 mutations between 2003 and 2010 were included in the study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status. Results Of 118 high-risk women with DCIS, 27% (n = 32) tested positive for BRCA1/BRCA2 mutations. Of those, 10% (n = 12) and 17% (n = 20) had BRCA1 and BRCA2 mutations, respectively. Age, race, and tumor characteristics did not differ between BRCA noncarriers and carriers. In a multivariate logistic model, ≥2 relatives with ovarian cancer (OC) (odds ratio [OR], 8.81; 95% confidence interval [CI], 1.38-56.29; P = .034), and a score ≥10% according to the BRCAPRO mathematical model for calculating the probability that a particular family member carries a germline BRCA mutation (OR, 6.37; 95% CI, 2.23-18.22; P = .0005) remained as independent significant predictors for a BRCA mutation. Fifty-seven percent of mutation carriers but only 25% of noncarriers underwent prophylactic mastectomy (P = .0037). This difference remained significant for patients aged ≤40 years (P = .025). Conclusions Women who had DCIS and a family history of OC or who had BRCAPRO scores ≥10% had a high rate of BRCA positivity regardless of age at diagnosis. These findings suggest that high-risk patients with DCIS are appropriate candidates for genetic testing for BRCA mutations in the presence of predictive factors even if they do not have invasive breast cancer. PMID:22009639

  19. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

    PubMed

    Im, Kate M; Kirchhoff, Tomas; Wang, Xianshu; Green, Todd; Chow, Clement Y; Vijai, Joseph; Korn, Joshua; Gaudet, Mia M; Fredericksen, Zachary; Shane Pankratz, V; Guiducci, Candace; Crenshaw, Andrew; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M; Mai, Phuong L; Greene, Mark H; Piedmonte, Marion; Rubinstein, Wendy S; Hogervorst, Frans B; Rookus, Matti A; Collée, J Margriet; Hoogerbrugge, Nicoline; van Asperen, Christi J; Meijers-Heijboer, Hanne E J; Van Roozendaal, Cees E; Caldes, Trinidad; Perez-Segura, Pedro; Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz; Blecharz, Paweł; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Barkardottir, Rosa B; Montagna, Marco; D'Andrea, Emma; Devilee, Peter; Olopade, Olufunmilayo I; Neuhausen, Susan L; Peissel, Bernard; Bonanni, Bernardo; Peterlongo, Paolo; Singer, Christian F; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda Ewart; Caligo, Maria Adelaide; Beattie, Mary S; Chan, Salina; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Phelan, Catherine; Narod, Steven; John, Esther M; Hopper, John L; Buys, Saundra S; Daly, Mary B; Southey, Melissa C; Terry, Mary-Beth; Tung, Nadine; Hansen, Thomas V O; Osorio, Ana; Benitez, Javier; Durán, Mercedes; Weitzel, Jeffrey N; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare T; Frost, Debra; Platte, Radka; Evans, D Gareth; Eeles, Ros; Izatt, Louise; Paterson, Joan; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J; Porteous, Mary; Walker, Lisa; Rogers, Mark T; Side, Lucy E; Godwin, Andrew K; Schmutzler, Rita K; Wappenschmidt, Barbara; Laitman, Yael; Meindl, Alfons; Deissler, Helmut; Varon-Mateeva, Raymonda; Preisler-Adams, Sabine; Kast, Karin; Venat-Bouvet, Laurence; Stoppa-Lyonnet, Dominique; Chenevix-Trench, Georgia; Easton, Douglas F; Klein, Robert J; Daly, Mark J; Friedman, Eitan; Dean, Michael; Clark, Andrew G; Altshuler, David M; Antoniou, Antonis C; Couch, Fergus J; Offit, Kenneth; Gold, Bert

    2011-11-01

    Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.

  20. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Im, Kate M.; Kirchhoff, Tomas; Wang, Xianshu; Green, Todd; Chow, Clement Y.; Vijai, Joseph; Korn, Joshua; Gaudet, Mia M.; Fredericksen, Zachary; Pankratz, V. Shane; Guiducci, Candace; Crenshaw, Andrew; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Mai, Phuong L.; Greene, Mark H.; Piedmonte, Marion; Rubinstein, Wendy S.; Hogervorst, Frans B.; Rookus, Matti A.; Collée, J. Margriet; Hoogerbrugge, Nicoline; van Asperen, Christi J.; Meijers-Heijboer, Hanne E. J.; Van Roozendaal, Cees E.; Caldes, Trinidad; Perez-Segura, Pedro; Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz; Blecharz, Paweł; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Barkardottir, Rosa B.; Montagna, Marco; D'Andrea, Emma; Devilee, Peter; Olopade, Olufunmilayo I.; Neuhausen, Susan L.; Peissel, Bernard; Bonanni, Bernardo; Peterlongo, Paolo; Singer, Christian F.; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda Ewart; Caligo, Maria Adelaide; Beattie, Mary S.; Chan, Salina; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Phelan, Catherine; Narod, Steven; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary-Beth; Tung, Nadine; Hansen, Thomas v. O.; Osorio, Ana; Benitez, Javier; Durán, Mercedes; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare T.; Frost, Debra; Platte, Radka; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Paterson, Joan; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary; Walker, Lisa; Rogers, Mark T.; Side, Lucy E.; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Laitman, Yael; Meindl, Alfons; Deissler, Helmut; Varon-Mateeva, Raymonda; Preisler-Adams, Sabine; Kast, Karin; Venat-Bouvet, Laurence; Stoppa-Lyonnet, Dominique; Chenevix-Trench, Georgia; Easton, Douglas F.; Klein, Robert J.; Daly, Mark J.; Friedman, Eitan; Dean, Michael; Clark, Andrew G.; Altshuler, David M.; Antoniou, Antonis C.; Couch, Fergus J.; Offit, Kenneth; Gold, Bert

    2011-01-01

    Abstract Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage dis-equilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews. PMID:21597964

  1. Bilateral Triple-Negative Invasive Breast Cancer with a BRCA2 Mutation, and Glioblastoma: A Case Report and Literature Review

    PubMed Central

    Alsharedi, Mohamed; Khelfa, Yousef; Tirona, Maria

    2017-01-01

    Breast cancer is the second leading cause of death among women in North America. Glioblastoma is the most common primary malignant central nervous system tumor in adults. The majority of hereditary breast cancers are associated with deleterious mutations in the BRCA1 and BRCA2 genes. Although few case reports have described the incidence of glioblastoma in patients previously diagnosed with breast cancer, any association between BRCA2 mutations and glioblastoma has not been demonstrated to date. Herein, we report a woman who is a carrier of a familial BRCA2 mutation, and was previously diagnosed with triple-negative breast cancer (TNBC) and subsequently with a second primary TNBC and glioblastoma. Further investigation is required to define the possible relationship between these two aggressive malignances and the BRCA2 mutation, which might be critical for the proper management and treatment of this disease. PMID:28382102

  2. Prostate cancer in a man with a BRCA2 mutation and a personal history of bilateral breast cancer.

    PubMed

    Singer, C F; Rappaport-Fuerhauser, C; Sopik, V; Narod, S A

    2015-08-01

    Men with a BRCA2 mutation face substantial lifetime risks for the development of both breast and prostate cancer. A male who was initially diagnosed with breast cancer at the age of 32 was subsequently diagnosed at age 77 with both contralateral breast cancer and prostate cancer. He was found to be BRCA2 mutation carrier. The patient was treated with contralateral mastectomy, breast irradiation, prostate irradiation and adjuvant endocrine therapy. At age 83 he died of metastatic prostate cancer. Our case underscores the observation that BRCA2 mutation carriers are at risk for multiple cancers, including contralateral breast cancer, and illustrates the need for current practice recommendations for the early detection of breast and prostate cancer in men with BRCA2 mutations.

  3. Frequent somatic loss of BRCA1 in breast tumours from BRCA2 germ-line mutation carriers and vice versa

    PubMed Central

    Staff, S; Isola, J J; Johannsson, O; Borg, Å; Tanner, M M

    2001-01-01

    Breast cancer susceptibility genes BRCA1 and BRCA2 are tumour suppressor genes the alleles of which have to be inactivated before tumour development occurs. Hereditary breast cancers linked to germ-line mutations of BRCA1 and BRCA2 genes almost invariably show allelic imbalance (AI) at the respective loci. BRCA1 and BRCA2 are believed to take part in a common pathway in maintenance of genomic integrity in cells. We carried out AI and fluorescence in situ hybridization (FISH) analyses of BRCA2 in breast tumours from germ-line BRCA1 mutation carriers and vice versa. For comparison, 14 sporadic breast tumours were also studied. 8 of the 11 (73%) informative BRCA1 mutation tumours showed AI at the BRCA2 locus. 53% of these tumours showed a copy number loss of the BRCA2 gene by FISH. 5 of the 6 (83%) informative BRCA2 mutation tumours showed AI at the BRCA1 locus. Half of the tumours (4/8) showed a physical deletion of the BRCA1 gene by FISH. Combined allelic loss of both BRCA1 and BRCA2 gene was seen in 12 of the 17 (71%) informative hereditary tumours, whereas copy number losses of both BRCA genes was seen in only 4/14 (29%) sporadic control tumours studied by FISH. In conclusion, the high prevalence of AI at BRCA1 in BRCA2 mutation tumours and vice versa suggests that somatic events occurring at the other breast cancer susceptibility gene locus may be selected in the cancer development. The mechanism resulting in AI at these loci seems more complex than a physical deletion.   http://www.bjcancer.com © 2001 Cancer Research Campaign PMID:11710835

  4. Mutations in BRCA1 and BRCA2 in breast cancer families: Are there more breast cancer-susceptibility genes?

    SciTech Connect

    Serova, O.M.; Mazoyer, S.; Putet, N.

    1997-03-01

    To estimate the proportion of breast cancer families due to BRCA1 or BRCA2, we performed mutation screening of the entire coding regions of both genes supplemented with linkage analysis of 31 families, 8 containing male breast cancers and 23 site-specific female breast cancer. A combination of protein-truncation test and SSCP or heteroduplex analyses was used for mutation screening complemented, where possible, by the analysis of expression level of BRCA1 and BRCA2 alleles. Six of the eight families with male breast cancer revealed frameshift mutations, two in BRCA1 and four in BRCA2. Although most families with female site-specific breast cancers were thought to be due to mutations in either BRCA1 or BRCA2, we identified only eight mutations in our series of 23 site-specific female breast cancer families (34%), four in BRCA1 and four in BRCA2. According to the posterior probabilities calculated for mutation-negative families, based on linkage data and mutation screening results, we would expect 8-10 site-specific female breast cancer families of our series to be due to neither BRCA1 nor BRCA2. Thus, our results suggest the existence of at least one more major breast cancer-susceptibility gene. 24 refs., 1 fig., 3 tabs.

  5. BRCA1 and BRCA2 Mutations in African Americans

    DTIC Science & Technology

    2000-10-01

    cancer syndromes that are prevalent among African Americans? Little information exists about other familial cancer syndromes unique to African...Americans but two African-American families with Cowden’s syndrome have been reported (Fackenthal et al, 2000). The same germline p53 coding mutation and...familial syndromes based on pedigree analysis, calculation of risk estimates, and effective communication of risk status at a level that the patient can

  6. Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations.

    PubMed

    Golmard, L; Delnatte, C; Laugé, A; Moncoutier, V; Lefol, C; Abidallah, K; Tenreiro, H; Copigny, F; Giraudeau, M; Guy, C; Barbaroux, C; Amorim, G; Briaux, A; Guibert, V; Tarabeux, J; Caputo, S; Collet, A; Gesta, P; Ingster, O; Stern, M-H; Rouleau, E; de Pauw, A; Gauthier-Villars, M; Buecher, B; Bézieau, S; Stoppa-Lyonnet, D; Houdayer, C

    2016-03-10

    BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.

  7. Contribution of BRCA1 and BRCA2 Mutations to Breast and Ovarian Cancer in Pakistan

    PubMed Central

    Liede, Alexander; Malik, Imtiaz A.; Aziz, Zeba; Rios, Patricia de los; Kwan, Elaine; Narod, Steven A.

    2002-01-01

    The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution that genetic factors make to these high rates, we have conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from two major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7% (95% confidence interval [CI] 4.1%–9.4%), and that among case subjects with ovarian cancer was 15.8% (95% CI 9.2%–22.4%). Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. The majority of detected mutations are unique to Pakistan. Five BRCA1 mutations (2080insA, 3889delAG, 4184del4, 4284delAG, and IVS14-1A→G) and one BRCA2 mutation (3337C→T) were found in multiple case subjects and represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 is comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1-mutation–positive case subjects was 48% and was 37% for first-degree relatives of the BRCA2-mutation–positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio [OR] 2.1; 95% CI 1.4–3.3; P=.001). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age <40 years) (OR=2.7; 95% CI 1.5–4.9; P=.0008) and case subjects with ovarian cancer (OR=2.4; 95% CI 1.4–4.2; P=.002). These results suggest that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan. PMID:12181777

  8. A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population

    PubMed Central

    2009-01-01

    Background In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated. Methods Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test. Results and Conclusion Overall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island (where a BRCA2 c.8764_8765delAG mutation with founder effect was predominant); b) the Middle area, land of the ancient Sardinian population (where BRCA2 mutations are still more common than BRCA1 mutations); and c) the South-Western area, with many Phoenician and Carthaginian locations (where BRCA1 mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of BRCA1-2 germline mutations. PMID:19619314

  9. Effect of BRCA2 mutation on familial breast cancer survival: A systematic review and meta-analysis.

    PubMed

    Shao, Jun; Yang, Jie; Wang, Jun-nai; Qiao, Long; Fan, Wei; Gao, Qing-lei; Feng, Yao-jun

    2015-10-01

    Reports of BRCA2 genetic mutations on the prognosis of familial breast cancer (BC) patients have been contradictory. True difference in survival, if it exists, would have important implications for genetic counseling and in treatment of hereditary BC. The purpose of this study was to compare overall survival rate (OSR) among BRCA2 mutation carriers, non-carriers and sporadic BC patients. We searched the PUBMED and EMBASE databases and retrieved 4529 articles using keywords that included breast cancer, BRCA, prognosis and survival. Nine articles were selected for systematic review and among them 6 were included in our meta-analysis. We used the fixed and random effect models to calculate the summary odds ratio (OR) and corresponding 95% confidence interval (CI). BRCA2 mutation carriers had significantly higher long-term OSR than non-carriers (OR=0.69 [95% CI=0.5-0.95]), while both short-term and long-term OSR of BRCA2 mutation carriers did not differ from those of patients with sporadic disease (OR=1.11 [95% CI=0.74-1.65]; 0.85 [95% CI=0.38-1.94], respectively). For BC-specific survival rate (BCSSR), BRCA2 mutation carriers had a similar BCSSR to the non-carriers (OR=0.61 [95% CI=0.28-1.34]). There was no significant difference in disease-free survival (DFS) between BRCA2 mutation carriers and patients with sporadic disease. Our results suggest that BRCA2 mutation increases long-term OSR in hereditary BC, which reminds us a new prospect of management of the disease.

  10. Prospective study of breast cancer risk for mutation negative women from BRCA1 or BRCA2 mutation positive families.

    PubMed

    Harvey, S L; Milne, R L; McLachlan, S A; Friedlander, M L; Birch, K E; Weideman, P; Goldgar, D; Hopper, J L; Phillips, K A

    2011-12-01

    Published studies have reached contradictory conclusions regarding breast cancer risk for women from families segregating a BRCA1 or BRCA2 mutation who do not carry the family-specific mutation. Accurate estimation of breast cancer risk is crucial for appropriate counselling regarding risk management. The aim of this study is to prospectively assess whether breast cancer risk for mutation negative women from families segregating BRCA1 or BRCA2 mutations is greater than for women in the general population. Eligible women were 722 first-, second- and third-degree relatives of a BRCA1 or BRCA2 mutation carrier from 224 mutation positive (128 BRCA1, 96 BRCA2) families, had no personal cancer history at baseline, and had been tested and found not to carry the family-specific mutation. Self-reported family history of cancer, preventive interventions and verified cancer diagnoses were collected at baseline, and every 3 years thereafter. Median follow-up was 6.1 years (range 0.1-12.4 years). Time at risk of breast cancer was censored at cancer diagnosis or risk-reducing surgery. Standardised incidence ratios (SIR) were estimated by comparing observed to population incidences of invasive breast cancer using Australian Cancer Incidence and Mortality Books. Six cases of invasive breast cancer were observed. The estimated SIRs were 1.14 (95% CI: 0.51-2.53) overall (n = 722), 1.29 (95% CI: 0.58-2.88) when restricted to first- and second-degree relatives of an affected mutation carrier (n = 442) and 0.48 (95% CI: 0.12-1.93) when restricted to those with no family history of breast cancer in the non-mutation carrying parental lineage (n = 424). There was no evidence that mutation negative women from families segregating BRCA1 or BRCA2 mutations are at increased risk of breast cancer. Despite this being the largest prospective cohort to assess this issue, moderately increased breast cancer risk (2-fold) cannot be ruled out.

  11. Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Kartsonaki, Christiana; Gayther, Simon A.; Pharoah, Paul D. P.; Sinilnikova, Olga M.; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Healey, Sue; Couch, Fergus J.; Wang, Xianshu; Fredericksen, Zachary; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Roversi, Gaia; Barile, Monica; Viel, Alessandra; Allavena, Anna; Ottini, Laura; Papi, Laura; Gismondi, Viviana; Capra, Fabio; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria Adelaide; Olsson, Håkan; Kristoffersson, Ulf; Lindblom, Annika; Arver, Brita; Karlsson, Per; Stenmark Askmalm, Marie; Borg, Ake; Neuhausen, Susan L.; Ding, Yuan Chun; Nathanson, Katherine L.; Domchek, Susan M.; Jakubowska, Anna; Lubiński, Jan; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Górski, Bohdan; Cybulski, Cezary; Dębniak, Tadeusz; Osorio, Ana; Durán, Mercedes; Tejada, Maria-Isabel; Benítez, Javier; Hamann, Ute; Rookus, Matti A.; Verhoef, Senno; Tilanus-Linthorst, Madeleine A.; Vreeswijk, Maaike P.; Bodmer, Danielle; Ausems, Margreet G. E. M.; van Os, Theo A.; Asperen, Christi J.; Blok, Marinus J.; Meijers-Heijboer, Hanne E. J.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Dunning, Alison M.; Evans, D. Gareth; Eeles, Ros; Pichert, Gabriella; Cole, Trevor; Hodgson, Shirley; Brewer, Carole; Morrison, Patrick J.; Porteous, Mary; Kennedy, M. John; Rogers, Mark T.; Side, Lucy E.; Donaldson, Alan; Gregory, Helen; Godwin, Andrew; Stoppa-Lyonnet, Dominique; Moncoutier, Virginie; Castera, Laurent; Mazoyer, Sylvie; Barjhoux, Laure; Bonadona, Valérie; Leroux, Dominique; Faivre, Laurence; Lidereau, Rosette; Nogues, Catherine; Bignon, Yves-Jean; Prieur, Fabienne; Collonge-Rame, Marie-Agnès; Venat-Bouvet, Laurence; Fert-Ferrer, Sandra; Miron, Alex; Buys, Saundra S.; Hopper, John L.; Daly, Mary B.; John, Esther M.; Terry, Mary Beth; Goldgar, David; Hansen, Thomas v. O.; Jønson, Lars; Ejlertsen, Bent; Agnarsson, Bjarni A.; Offit, Kenneth; Kirchhoff, Tomas; Vijai, Joseph; Dutra-Clarke, Ana V. C.; Przybylo, Jennifer A.; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny N.; Janavicius, Ramunas; Blanco, Ignacio; Lázaro, Conxi; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Beattie, Mary S.; Schmutzler, Rita; Wappenschmidt, Barbara; Meindl, Alfons; Ruehl, Ina; Fiebig, Britta; Sutter, Christian; Arnold, Norbert; Deissler, Helmut; Varon-Mateeva, Raymonda; Kast, Karin; Niederacher, Dieter; Gadzicki, Dorothea; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Simard, Jacques; Soucy, Penny; Spurdle, Amanda B.; Holland, Helene; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.

    2011-01-01

    Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. Methods We genotyped rs3814113 in 10 029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. Results The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. Conclusion Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation. PMID:21169536

  12. Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene.

    PubMed

    Degrolard-Courcet, Emilie; Sokolowska, Joanna; Padeano, Marie-Martine; Guiu, Séverine; Bronner, Myriam; Chery, Carole; Coron, Fanny; Lepage, Côme; Chapusot, Caroline; Loustalot, Catherine; Jouve, Jean-Louis; Hatem, Cyril; Ferrant, Emmanuelle; Martin, Laurent; Coutant, Charles; Baurand, Amandine; Couillault, Gérard; Delignette, Alexandra; El Chehadeh, Salima; Lizard, Sarab; Arnould, Laurent; Fumoleau, Pierre; Callier, Patrick; Mugneret, Francine; Philippe, Christophe; Frebourg, Thierry; Jonveaux, Philippe; Faivre, Laurence

    2014-08-01

    Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.

  13. The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry.

    PubMed

    Peixoto, A; Santos, C; Pinto, P; Pinheiro, M; Rocha, P; Pinto, C; Bizarro, S; Veiga, I; Principe, A S; Maia, S; Castro, F; Couto, R; Gouveia, A; Teixeira, M R

    2015-07-01

    We report the analysis of altogether 1050 suspected hereditary breast/ovarian cancer (HBOC) families, 524 fully screened for BRCA1/BRCA2 mutations and 526 tested only for the most common mutations. Of the 119 families with pathogenic mutations, 40 (33.6%) had the BRCA2 c.156_157insAlu rearrangement and 15 (12.6%) the BRCA1 c.3331_3334del mutation, the former being specific of Portuguese ancestry and the latter showing a founder effect in Portugal. Interestingly, the two most common mutations were found in a significant proportion of the HBOC families with an a priori BRCAPRO mutation probability <10%. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry, even those fulfilling moderately stringent clinical-criteria for genetic testing, should be specifically analyzed for the two most common BRCA1/BRCA2 founder mutations, and we here present a simple method for this first tier test. Screening of the entire coding regions of BRCA1 and BRCA2 should subsequently be offered to those families with a mutation probability ≥10% if none of those founder mutations are found.

  14. Breast Cancer Incidence After Risk-Reducing Salpingo-Oophorectomy in BRCA1 and BRCA2 Mutation Carriers.

    PubMed

    Fakkert, Ingrid E; Mourits, Marian J E; Jansen, Liesbeth; van der Kolk, Dorina M; Meijer, Kees; Oosterwijk, Jan C; van der Vegt, Bert; Greuter, Marcel J W; de Bock, Geertruida H

    2012-11-01

    Premenopausal risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers effectively reduces ovarian cancer risk, but also reduces breast cancer risk. Breast cancer risk reductions up to 50% have been reported for both BRCA1 and BRCA2 mutation carriers, but recent prospective studies were not able to reproduce this finding for BRCA1 mutation carriers. Breast cancer incidence after RRSO was assessed in a consecutive series of 104 BRCA1 and 58 BRCA2 mutation carriers. On the basis of data from our own centre, and assuming a 50% risk reduction through RRSO at premenopausal age, we expected to find 8 breast cancers (range 6-10) in this population for the reported screening period (532 women-years). In 162 carriers with a median age of 41 years at RRSO, 13 incident breast cancers were diagnosed. In BRCA1 mutation carriers, 12 incident breast cancers were found compared with 5 (range 3-6) expected and in BRCA2 mutation carriers 1 breast cancer was found compared with 3 (range 2-5) expected. Breast cancer incidence after premenopausal RRSO is still high, especially in BRCA1 mutation carriers. Previously reported breast cancer risk reductions up to 50% were not confirmed. As a consequence, continued intensive screening for breast cancer is warranted in BRCA1 and BRCA2 mutation carriers after RRSO.

  15. BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2.

    PubMed Central

    Schubert, E L; Lee, M K; Mefford, H C; Argonza, R H; Morrow, J E; Hull, J; Dann, J L; King, M C

    1997-01-01

    In order to evaluate the role of inherited BRCA2 mutations in American families--particularly the appearance in America of European founder mutations--the BRCA2 coding sequence, 5' UTR, and 3' UTR were screened in 22 Caucasian American kindreds with four or more cases of breast or ovarian cancer. Six mutations were found that cause a premature-termination codon; four of them have been reported elsewhere, and two are novel. In the four families with previously seen mutations, the distinct lineages at high risk of cancer were of Dutch, German, Irish, and Ashkenazi Jewish ancestry; mutations in Europe reflect these ancestries. The families with novel mutations were Puerto Rican Hispanic (exon 9 deletion 995delCAAAT) and Ashkenazi Jewish (exon 11 deletion 6425delTT). Among female BRCA2-mutation carriers, risks of breast cancer were 32% by age 50 years, 67% by age 70 years, and 80% by age 90 years, yielding a lifetime risk similar to that for BRCA1 but an older distribution of ages at onset. BRCA2 families also included multiple cases of cancers of the male breast (six cases), ovary (three cases), fallopian tube (two cases), pancreas (three cases), bladder (two cases), and prostate (two cases). Among 17 Ashkenazi Jewish families with four or more breast or ovarian cancers, 9 families (including 3 with ovarian cancer and 1 with male breast cancer) carried none of the three ancient mutations in BRCA1 or BRCA2. To date, both BRCA2 and BRCA1 have been screened by SSCA, supplemented by the protein-truncation test, in 48 families with four or more breast or ovarian cancers. Mutations have been detected in BRCA1 in 33 families, in BRCA2 in 6 families, and in neither gene in 9 families, suggesting both the probable cryptic nature of some mutations and the likelihood of at least one other BRCA gene. PMID:9150150

  16. Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families from Asturias (Northern Spain)

    PubMed Central

    2013-01-01

    Background The prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families. The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain). Methods In the present work, 256 unrelated high-risk probands with breast and/or ovarian cancer from families living in Asturias were analyzed for the presence of a BRCA1 or BRCA2 gene mutation from October 2007 to May 2012. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened both by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). Results A total of 59 families (23%) were found to carry a pathogenic germ line mutation, 39 in BRCA1 and 20 in BRCA2. Twenty nine additional families (12%) carried an unknown significance variant. We detected 28 distinct pathogenic mutations (16 in BRCA1 and 12 in BRCA2), of which 3 mutations in BRCA1 (c.1674delA, c.1965C>A and c.2900_2901dupCT) and 5 in BRCA2 (c.262_263delCT, c.2095C>T, c.3263dupC, c.4030_4035delinsC, c.8042_8043delCA) had not been previously described. The novel mutations c.2900_2901dupCT in BRCA1 and c.4030_4035delinsC in BRCA2 occurred in 8 and 6 families respectively and clustered in two separated small geographically isolated areas suggesting a founder effect. These 2 mutations, together with the Galician BRCA1 mutation c.211A>G (9 families), and the common BRCA1 mutation c.3331_3334delCAAG (6 families), account for approximately 50% of all affected families. By contrast, very frequent mutations in other Spanish series such as the BRCA1 Ashkenazi founder mutation c.68_69delAG, was found in only one family. Conclusions In this study we report the BRCA1 and BRCA2 spectrum of mutations and their geographical distribution in Asturias, which largely differ from other areas of Spain. Our findings may help design a first step recurrent mutation panel for

  17. Increased Chromosomal Radiosensitivity in Women Carrying BRCA1/BRCA2 Mutations Assessed With the G2 Assay

    SciTech Connect

    Ernestos, Beroukas; Nikolaos, Pandis; Koulis, Giannoukakos; Eleni, Rizou; Konstantinos, Beroukas; Alexandra, Giatromanolaki; Michael, Koukourakis

    2010-03-15

    Purpose: Several in vitro studies suggest that BRCA1 and BRCA2 mutation carriers present increased sensitivity to ionizing radiation. Different assays for the assessment of deoxyribonucleic acid double-strand break repair capacity have been used, but results are rather inconsistent. Given the concerns about the possible risks of breast screening with mammography in mutation carrier women and the potentially damaging effects of radiotherapy, the purpose of this study was to further investigate the radiosensitivity of this population. Methods and Materials: The G2 chromosomal radiosensitivity assay was used to assess chromosomal breaks in lymphocyte cultures after exposure to 1 Gy. A group of familiar breast cancer patients carrying a mutation in the BRCA1 or BRCA2 gene (n = 15) and a group of healthy mutation carriers (n = 5) were investigated and compared with a reference group of healthy women carrying no mutation (n = 21). Results: BRCA1 and BRCA2 mutation carriers had a significantly higher number of mean chromatid breaks per cell (p = 0.006) and a higher maximum number of breaks (p = 0.0001) as compared with their matched controls. Both healthy carriers and carriers with a cancer history were more radiosensitive than controls (p = 0.002 and p = 0.025, respectively). Age was not associated with increased radiosensitivity (p = 0.868). Conclusions: Our results indicate that BRCA1 and BRCA2 mutation carriers show enhanced radiosensitivity, presumably because of the involvement of the BRCA genes in deoxyribonucleic acid repair and cell cycle control mechanisms.

  18. BRCA1 and BRCA2 Mutations in Ethnic Lebanese Arab Women With High Hereditary Risk Breast Cancer

    PubMed Central

    Zgheib, Nathalie K.; Assi, Hussein A.; Khoury, Katia E.; Bidet, Yannick; Jaber, Sara M.; Charara, Raghid N.; Farhat, Rania A.; Kreidieh, Firas Y.; Decousus, Stephanie; Romero, Pierre; Nemer, Georges M.; Salem, Ziad; Shamseddine, Ali; Tfayli, Arafat; Abbas, Jaber; Jamali, Faek; Seoud, Muhieddine; Armstrong, Deborah K.; Bignon, Yves-Jean; Uhrhammer, Nancy

    2015-01-01

    Purpose. Breast cancer is the most common malignancy among women in Lebanon and in Arab countries, with 50% of cases presenting before the age of 50 years. Methods. Between 2009 and 2012, 250 Lebanese women with breast cancer who were considered to be at high risk of carrying BRCA1 or BRCA2 mutations because of presentation at young age and/or positive family history (FH) of breast or ovarian cancer were recruited. Clinical data were analyzed statistically. Coding exons and intron-exon boundaries of BRCA1 and BRCA2 were sequenced from peripheral blood DNA. All patients were tested for BRCA1 rearrangements using multiplex ligation-dependent probe amplification (MLPA). BRCA2 MLPA was done in selected cases. Results. Overall, 14 of 250 patients (5.6%) carried a deleterious BRCA mutation (7 BRCA1, 7 BRCA2) and 31 (12.4%) carried a variant of uncertain significance. Eight of 74 patients (10.8%) aged ≤40 years with positive FH and only 1 of 74 patients (1.4%) aged ≤40 years without FH had a mutated BRCA. Four of 75 patients (5.3%) aged 41–50 years with FH had a deleterious mutation. Only 1 of 27 patients aged >50 years at diagnosis had a BRCA mutation. All seven patients with BRCA1 mutations had grade 3 infiltrating ductal carcinoma and triple-negative breast cancer. Nine BRCA1 and 17 BRCA2 common haplotypes were observed. Conclusion. Prevalence of deleterious BRCA mutations is lower than expected and does not support the hypothesis that BRCA mutations alone cause the observed high percentage of breast cancer in young women of Lebanese and Arab descent. Studies to search for other genetic mutations are recommended. PMID:25777348

  19. Disseminated Medulloblastoma in a Child with Germline BRCA2 6174delT Mutation and without Fanconi Anemia

    PubMed Central

    Xu, Jingying; Margol, Ashley Sloane; Shukla, Anju; Ren, Xiuhai; Finlay, Jonathan L.; Krieger, Mark D.; Gilles, Floyd H.; Couch, Fergus J.; Aziz, Meraj; Fung, Eric T.; Asgharzadeh, Shahab; Barrett, Michael T.; Erdreich-Epstein, Anat

    2015-01-01

    Medulloblastoma, the most common malignant brain tumor in children, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2. We describe an 8-year-old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented 8 months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here, we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization, and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2, and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia. PMID:26380221

  20. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B.; Rudolph, Anja; Schmutzler, Rita K.; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A.; Easton, Douglas F.; Hamann, Ute; Wilkening, Stefan; Chen, Bowang; Rookus, Matti A.; Schmidt, Marjanka K; van der Baan, Frederieke H.; Spurdle, Amanda B.; Walker, Logan C.; Lose, Felicity; Maia, Ana-Teresa; Montagna, Marco; Matricardi, Laura; Lubinski, Jan; Jakubowska, Anna; Gómez Garcia, Encarna B.; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K.; Miron, Alex; Southey, Melissa C.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Ding, Yuan Chun; Neuhausen, Susan L.; Hansen, Thomas V. O.; Gerdes, Anne-Marie; Ejlertsen, Bent; Jønson, Lars; Osorio, Ana; Martínez-Bouzas, Cristina; Benitez, Javier; Conway, Edye E.; Blazer, Kathleen R.; Weitzel, Jeffrey N.; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Martayan, Aline; Tibiletti, Maria Grazia; Radice, Paolo; Vratimos, Athanassios; Fostira, Florentia; Garber, Judy E.; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D. Gareth R.; Frost, Debra; Eccles, Diana; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E.; Kennedy, M. John; Rogers, Mark T.; Porteous, Mary E.; Morrison, Patrick J.; Platte, Radka; Davidson, Rosemarie; Hodgson, Shirley V.; Ellis, Steve; Cole, Trevor; Godwin, Andrew K.; Claes, Kathleen; Van Maerken, Tom; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wang-Gohrke, Shan; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Boutry-Kryza, Nadia; Sinilnikova, Olga M.; Caron, Olivier; Pujol, Pascal; Mazoyer, Sylvie; Belotti, Muriel; Piedmonte, Marion; Friedlander, Michael L.; Rodriguez, Gustavo C.; Copeland, Larry J; de la Hoya, Miguel; Segura, Pedro Perez; Nevanlinna, Heli; Aittomäki, Kristiina; van Os, Theo A.M.; Meijers-Heijboer, Hanne E.J.; van der Hout, Annemarie H.; Vreeswijk, Maaike P.G.; Hoogerbrugge, Nicoline; Ausems, Margreet G.E.M.; van Doorn, Helena C.; Collée, J. Margriet; Olah, Edith; Diez, Orland; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Feliubadalo, Lidia; Cybulski, Cezary; Gronwald, Jacek; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Sukiennicki, Grzegorz; Arason, Adalgeir; Chiquette, Jocelyne; Teixeira, Manuel R.; Olswold, Curtis; Couch, Fergus J.; Lindor, Noralane M.; Wang, Xianshu; Szabo, Csilla I.; Offit, Kenneth; Corines, Marina; Jacobs, Lauren; Robson, Mark E.; Zhang, Liying; Joseph, Vijai; Berger, Andreas; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M.; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Mulligan, Anna Marie; Glendon, Gord; Tchatchou, Sandrine; Andrulis, Irene L.; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Laitman, Yael; Rantala, Johanna; von Wachenfeldt, Anna; Ehrencrona, Hans; Askmalm, Marie Stenmark; Borg, Åke; Kuchenbaecker, Karoline B.; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Friedman, Eitan

    2014-01-01

    Background BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. PMID:25336561

  1. Low prevalence of HER2 positivity amongst BRCA1 and BRCA2 mutation carriers and in primary BRCA screens.

    PubMed

    Evans, D G; Lalloo, F; Howell, S; Verhoef, S; Woodward, E R; Howell, A

    2016-02-01

    The aim of this study is to delineate more clearly the prevalence of HER2+ breast cancer in women with germline BRCA1/2 mutations. For this purpose, we analysed primary mutation screens on women with breast cancer with unequivocal HER2 amplification and assessed the proportion of BRCA1 and BRCA2 breast cancers that were HER2+ comparing this with the existing literature. The results are that 1063 primary BRCA screens had confirmed tumour HER2 status. If HER2+ only 2.5 % (4/156) and 3.2 % (5/156) of women had a BRCA1 or BRCA2 mutation identified respectively; compared to 27.7 % (115/415) and 8.2 % (34/415) with triple negative tumours. Only 2.1 % (4/195) women with BRCA1-related breast cancer had HER2 amplified breast cancers rising to 6.8 % (n = 12, p = 0.04) in BRCA2. These rates are in keeping with most of the existing literature except a recent large multicenter report which documented higher rates but with no control group. The study concluded that true HER2-amplified breast cancers are rare amongst BRCA1 mutation carriers and are less common in BRCA2 than background rates.

  2. Mammography screening and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers: a prospective study.

    PubMed

    Giannakeas, Vasily; Lubinski, Jan; Gronwald, Jacek; Moller, Pal; Armel, Susan; Lynch, Henry T; Foulkes, William D; Kim-Sing, Charmaine; Singer, Christian; Neuhausen, Susan L; Friedman, Eitan; Tung, Nadine; Senter, Leigha; Sun, Ping; Narod, Steven A

    2014-08-01

    Women with a genetic predisposition to breast cancer may be at increased risk of cancer after exposure to ionizing radiation. It is unclear whether mammography screening increases the risk of breast cancer among BRCA1 and BRCA2 carriers. We identified 2,346 women with a BRCA1 (n = 1844) or BRCA2 (n = 502) mutation and no breast cancer, and we reviewed their history of mammography exposure. These women were followed for an average of 5.3 years and were observed for new breast cancer diagnoses. At study entry, 1808 women (77.1 %) reported ever having had a mammogram; of these, 204 women (11.2 %) reported having had a mammogram before age 30. We estimated the hazard ratios for the development of invasive breast cancer, conditional on the number of prior mammograms and on the age at first mammogram. Hazard ratios were estimated and stratified by gene (BRCA1 or BRCA2), relative to women with no exposure. We observed no significant association between prior mammography exposure and breast cancer risk for BRCA1 carriers (HR 0.79; 95 % CI 0.53-1.19; P = 0.26) or for BRCA2 carriers (HR 0.90; 95 % CI 0.35-2.34; P = 0.83). An early age at first mammogram (<30 years) did not increase breast cancer risk among BRCA1 carriers (HR 0.75; 95 % CI 0.41-1.37; P = 0.35) or among BRCA2 carriers (HR 0.69; 95 % CI 0.19-2.48; P = 0.57). Exposure to mammography in women with BRCA1 and BRCA2 mutations is not associated with an increased risk of breast cancer.

  3. Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from medellín, Colombia

    PubMed Central

    2014-01-01

    Background Approximately 5% of all breast cancers can be attributed to a mutation in the BRCA1 or BRCA2 gene. The genetic component of breast cancer in Colombia has been, for the most part, studied on cases from the Bogota region. Five different founder mutations were in two studies of breast cancer patients in the Bogota region. It is important that the frequency of mutations be established among unselected cases of breast cancer of other regions of Colombia in order to estimate the genetic burden of this cancer in Colombia and to plan genetic services. The aim of this study was to establish the mutation frequencies of the BRCA genes in breast cancer patients unselected for family history or age, from Medellin, Colombia. Methods We enrolled 280 unselected women with breast cancer from a large public hospital in Medellin, Colombia. A detailed family history from each patient and a blood sample was obtained and processed for DNA analysis. Mutations in BRCA1 and BRCA2 were sought using a combination of techniques including a panel of recurrent Hispanic BRCA mutations which consists of fifty BRCA1 mutations and forty-six BRCA2 mutations, including the five recurrent Colombian BRCA mutations. All mutations were confirmed by direct sequencing. Results Genetic testing was successfully completed for 244 of the 280 cases (87%). Among the 244 cases, three deleterious mutations were identified (two in BRCA1 and one in BRCA2) representing 1.2% of the total. The average age of breast cancer in the mutation-positive cases was 34 years. The two BRCA1 mutations were known founder mutations (3450del4 in exon 11 and A1708E in exon 18). The BRCA2 mutation was in exon 11 (5844del5) and has not been previously reported in individuals of Colombian descent. Among the three mutation-positive families was a breast cancer family and two families with no history of breast or ovarian cancer. Conclusion The frequency of BRCA mutations in unselected breast cancer cases from the Medellin region

  4. Analysis of chromosomal radiosensitivity of healthy BRCA2 mutation carriers and non-carriers in BRCA families with the G2 micronucleus assay

    PubMed Central

    Baert, Annelot; Depuydt, Julie; Van Maerken, Tom; Poppe, Bruce; Malfait, Fransiska; Van Damme, Tim; De Nobele, Sylvia; Perletti, Gianpaolo; De Leeneer, Kim; Claes, Kathleen B.M.; Vral, Anne

    2017-01-01

    Breast cancer risk drastically increases in individuals with a heterozygous germline BRCA1 or BRCA2 mutation, while it is estimated to equal the population risk for relatives without the familial mutation (non-carriers). The aim of the present study was to use a G2 phase-specific micronucleus assay to investigate whether lymphocytes of healthy BRCA2 mutation carriers are characterized by increased radiosensitivity compared to controls without a family history of breast/ovarian cancer and how this relates to healthy non-carrier relatives. BRCA2 is active in homologous recombination, a DNA damage repair pathway, specifically active in the late S/G2 phase of the cell cycle. We found a significantly increased radiosensitivity in a cohort of healthy BRCA2 mutation carriers compared to individuals without a familial history of breast cancer (P=0.046; Mann-Whitney U test). At the individual level, 50% of healthy BRCA2 mutation carriers showed a radiosensitive phenotype (radiosensitivity score of 1 or 2), whereas 83% of the controls showed no radiosensitivity (P=0.038; one-tailed Fishers exact test). An odds ratio of 5 (95% CI, 1.07–23.47) indicated an association between the BRCA2 mutation and radiosensitivity in healthy mutation carriers. These results indicate the need for the gentle use of ionizing radiation for either diagnostic or therapeutic use in BRCA2 mutation carriers. We detected no increased radiosensitivity in the non-carrier relatives. PMID:28184943

  5. BRCA1, BRCA2, PALB2, and CDKN2A Mutations in Familial Pancreatic Cancer (FPC): A PACGENE Study

    PubMed Central

    Zhen, David B.; Rabe, Kari G.; Gallinger, Steven; Syngal, Sapna; Schwartz, Ann G.; Goggins, Michael G.; Hruban, Ralph H.; Cote, Michele L.; McWilliams, Robert R.; Roberts, Nicholas J.; Cannon-Albright, Lisa A.; Li, Donghui; Moyes, Kelsey; Wenstrup, Richard J.; Hartman, Anne-Renee; Seminara, Daniela; Klein, Alison P.; Petersen, Gloria M.

    2014-01-01

    Purpose Familial Pancreatic Cancer (FPC) kindreds contain at least two affected first-degree relatives (FDR). Comprehensive data are needed to assist clinical risk assessment and genetic testing. Methods Germline DNA samples from 727 unrelated probands with positive family history (521 met criteria for FPC) were CLIA-tested for mutations in BRCA1 and BRCA2 (including analysis of deletions and rearrangements), PALB2, and CDKN2A. We compared prevalence of deleterious mutations between FPC probands and non-FPC probands (kindreds containing at least two affected biologic relatives, but not FDR). We also examined the impact of family history of breast and ovarian cancer and melanoma. Results Prevalence of deleterious mutations (excluding variants of unknown significance) among FPC probands was: BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; CDKN2A, 2.5%. Four novel deleterious mutations were detected. FPC probands carry more mutations in the four genes (8.0%) than non-FPC probands (3.5%) (odds ratio=2.40, 95% CI=(1.06, 5.44), p=0.03). The probability of testing positive for deleterious mutations in any of the four genes ranges up to 10.4%, depending upon family history of cancers. BRCA2 and CDKN2A account for the majority of mutations in FPC. Conclusion Genetic testing of multiple relevant genes in probands with a positive family history is warranted, particularly for FPC. PMID:25356972

  6. Cancers Associated with BRCA1 and BRCA2 Mutations other than Breast and Ovarian

    PubMed Central

    Mersch, Jacqueline; Jackson, Michelle; Park, Minjeong; Nebgen, Denise; Peterson, Susan K.; Singletary, Claire; Arun, Banu K.; Litton, Jennifer K.

    2014-01-01

    Background Previous studies have reported additional cancers associated with BRCA mutations; however, type, magnitude of risk, and gender differences remain to be clarified. The purpose of this study was to evaluate the incidence of cancers other than breast and ovarian cancer in known mutation carriers. Methods An institutional review board approved study identified 1072 patients who had genetic counseling at our institution and tested positive for a deleterious BRCA mutation. The expected number of cancer cases was calculated from the number of individuals in the study sample multiplied by the general population cancer incidence rates. The expected and observed number of cases were calculated in 5 year intervals to accommodate different age-related incidence rates. Standardized incidence ratios (SIRs) for each cancer type were calculated. Results We identified 1177 cancers in the 1072 mutation carriers comprising 30 different cancer types. Individuals with a BRCA1 mutation did not have a significant increase in cancers other than breast and ovarian; however, a trend in melanoma was observed. Individuals with a BRCA2 mutation had a significantly higher number of observed cases compared to expected cases for pancreatic cancer (SIR = 21.7, 95%CI = 13.1–34.0, p value <0.001) in both men and women and prostate cancer in men (SIR = 4.9, 95%CI = 2.0–10.1, p value =0.002). Conclusions The results of this study uphold the current recommendations for HBOC screening of cancers other than breast and ovarian by the National Comprehensive Cancer Network. Larger cohorts and collaborations are needed to further verify these findings. PMID:25224030

  7. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Ramus, Susan J; Antoniou, Antonis C; Kuchenbaecker, Karoline B; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E; Aalfs, Cora M; Meijers-Heijboer, Hanne E J; van Asperen, Christi J; van Roozendaal, K E P; Hoogerbrugge, Nicoline; Collée, J Margriet; Kriege, Mieke; van der Luijt, Rob B; Peock, Susan; Frost, Debra; Ellis, Steve D; Platte, Radka; Fineberg, Elena; Evans, D Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J; Walker, Lisa; Porteous, Mary E; Kennedy, M John; Pathak, Harsh; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v O; Ejlertsen, Bent; Johannsson, Oskar Th; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; Van Le, Linda; Hoffman, James S; Ewart Toland, Amanda; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Issacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Iganacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B; Karlan, Beth Y; Gross, Jenny; Olah, Edith; Vaszko, Tibor; Teo, Soo-Hwang; Ganz, Patricia A; Beattie, Mary S; Dorfling, Cecelia M; van Rensburg, Elizabeth J; Diez, Orland; Kwong, Ava; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B; Neuhausen, Susan L; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H; Mai, Phuong L; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D P; Gayther, Simon A; Simard, Jacques; Easton, Douglas F; Couch, Fergus J; Chenevix-Trench, Georgia

    2012-04-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

  8. Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico

    PubMed Central

    Villarreal-Garza, Cynthia; Alvarez-Gómez, Rosa María; Pérez-Plasencia, Carlos; Herrera, Luis A.; Herzog, Josef; Castillo, Danielle; Mohar, Alejandro; Castro, Clementina; Gallardo, Lenny N.; Gallardo, Dolores; Santibáñez, Miguel; Blazer, Kathleen R.; Weitzel, Jeffrey N.

    2014-01-01

    Background Frequent recurrent BRCA1 and BRCA2 gene (BRCA) mutations among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 ex9-12del), suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling economical screening for hereditary breast and ovarian cancer in Mexico. Methods In a multistage approach, 188 cancer cases unselected for family cancer history (92 ovarian cancer and 96 breast cancer) were screened for BRCA mutations using a Hispanic mutation panel (HISPANEL®) of 115 recurrent mutations in a multiplex assay (114 on a mass spectroscopy platform, and a PCR assay for the BRCA1 ex9-12del mutation), followed by sequencing of all BRCA exons and adjacent intronic regions, and BRCA1 multiplex ligation-dependent probe amplification assay (MLPA) for HISPANEL negative cases. BRCA mutation prevalence was calculated and correlated with histology and tumor receptor status, and HISPANEL sensitivity was estimated. Results BRCA mutations were detected in 28% (26/92) of ovarian cancer cases and 15% (14/96) of breast cancer cases overall and 27% (9/33) of triple negative breast cancer. Most breast cancer cases were diagnosed with locally advanced disease. The Mexican founder mutation (BRCA1 ex9-12del) accounted for 35% of the BRCA-associated ovarian cancer cases and 29% of the BRCA-associated breast cancer cases. At 2% of the sequencing and MLPA cost, the HISPANEL detected 68% of all BRCA mutations. Conclusion In this study, we found a remarkably high prevalence of BRCA mutations among ovarian and breast cases not selected for family history, and BRCA1 ex9-12del explained one third of the total. The remarkable frequency of BRCA1 ex9-12del in Mexico City supports a nearby origin of this Mexican founder mutation and may constitute a regional public health problem. The HISPANEL presents a translational opportunity for cost-effective genetic testing to enable breast and ovarian cancer

  9. Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

    PubMed Central

    Rebbeck, Timothy R.; Mitra, Nandita; Wan, Fei; Sinilnikova, Olga M.; Healey, Sue; McGuffog, Lesley; Mazoyer, Sylvie; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.; Nathanson, Katherine L.

    2015-01-01

    IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES Breast and ovarian cancer risks. RESULTS Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22–1.74; P = 2 × 10−6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01–1.78; P = .04), and c. 5261 to c.5563 (BCCR23, RHR = 1.38; 95% CI, 1.22–1.55; P = 6 × 10−9). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56–0.70; P = 9 × 10−17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06–2.78; P = .03), c.772 to c.1806 (BCCR13; RHR = 1.63; 95% CI, 1.10–2.40; P = .01

  10. The prevalence of BRCA1 and BRCA2 mutations among young Mexican women with triple-negative breast cancer

    PubMed Central

    Villarreal-Garza, C.; Weitzel, J. N.; Llacuachaqui, M.; Sifuentes, E.; Magallanes-Hoyos, M. C.; Gallardo, L.; Alvarez-Gómez, R. M.; Herzog, J.; Castillo, D.; Royer, R.; Akbari, Mohammad; Lara-Medina, F.; Herrera, L. A.; Mohar, A.

    2015-01-01

    Various guidelines recommend that women with triple-negative breast cancer should be tested for BRCA1 mutations, but the prevalence of mutations may vary with ethnic group and with geographic region, and the optimal cutoff age for testing has not been established. We estimated the frequencies of BRCA1 and BRCA2 (BRCA) mutations among 190 women with triple-negative breast cancer, unselected for family history, diagnosed at age 50 or less at a single hospital in Mexico City. Patients were screened for 115 recurrent BRCA mutations, which have been reported previously in women of Hispanic origin, including a common large rearrangement Mexican founder mutation (BRCA1 ex9-12del). A BRCA mutation was detected in 44 of 190 patients with triple-negative breast cancer (23 %). Forty-three mutations were found in BRCA1 and one mutation was found in BRCA2. Seven different mutations accounted for 39 patients (89 % of the total mutations). The Mexican founder mutation (BRCA1 ex9-12del) was found 18 times and accounted for 41 % of all mutations detected. There is a high prevalence of BRCA1 mutations among young triple-negative breast cancer patients in Mexico. Women with triple-negative breast cancer in Mexico should be screened for mutations in BRCA1. PMID:25716084

  11. Predictors of cognitive appraisals following genetic testing for BRCA1 and BRCA2 mutations.

    PubMed

    Halbert, Chanita Hughes; Schwartz, Marc D; Wenzel, Lari; Narod, Steven; Peshkin, Beth N; Cella, David; Lerman, Caryn

    2004-08-01

    The objectives of this study were (1) to describe perceptions of stress and confidence following genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations and (2) to identify predictors of these processes. Participants were 130 high-risk women affected with cancer who received BRCA1/2 test results. Individual difference characteristics and interpersonal factors were measured by self-report before genetic counseling and perceptions of stress and confidence were evaluated by self-report 1 month following disclosure of test results. BRCA1/2 test results had a significant effect only on perceptions of stress (beta = 0.38, p = 0.0001), while trait anxiety had a significant effect on both perceptions of stress (beta = 0.44, p = 0.0001) and confidence (beta = -0.41, p = 0.001). These results suggest that interventions designed to address perceptions of stress related to medical decision-making and familial concerns may need to be targeted to BRCA1/2 mutation carriers and individuals who are highly anxious.

  12. BRCA1 and BRCA2 germ-line mutations and oral contraceptives: to use or not to use.

    PubMed

    Grenader, Tal; Peretz, Tamar; Lifchitz, Meyer; Shavit, Linda

    2005-08-01

    Approximately 10% of the cases of breast cancer and invasive ovarian cancer are hereditary, occurring predominantly in women with germ-line mutations in the BRCA1 or BRCA2 gene. In deciding whether women with germ-line mutations in the BRCA1 gene should use oral contraceptives a possible increase in the risk of breast cancer needs to be weighed against the convenience of this means of birth control and its potential to reduce the risk of ovarian cancer. In women with BRCA2 mutations, oral contraceptive use has not been associated with an increased risk of breast cancer and does have the potential to reduce the risk of ovarian cancer. Prophylactic surgical options and intensified surveillance should, of course, be discussed with these patients.

  13. The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Laitman, Yael; Kuchenbaecker, Karoline B.; Rantala, Johanna; Hogervorst, Frans; Peock, Susan; Godwin, Andrew K.; Arason, Adalgeir; Kirchhoff, Tomas; Offit, Kenneth; Isaacs, Claudine; Schmutzler, Rita K.; Wappenschmidt, Barbara; Nevanlinna, Heli; Chen, Xiaoqing; Chenevix-Trench, Georgia; Healey, Sue; Couch, Fergus; Peterlongo, Paolo; Radice, Paolo; Nathanson, Katherine L.; Caligo, Maria Adelaide; Neuhausen, Susan L.; Ganz, Patricia; Sinilnikova, Olga M.; McGuffog, Lesley; Easton, Douglas F.; Antoniou, Antonis C.; Wolf, Ido

    2012-01-01

    Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan® allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93–1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82–1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84–1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66–1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. PMID:22212556

  14. Rapid and cost-effective high-throughput sequencing for identification of germline mutations of BRCA1 and BRCA2.

    PubMed

    Ahmadloo, Somayeh; Nakaoka, Hirofumi; Hayano, Takahide; Hosomichi, Kazuyoshi; You, Hua; Utsuno, Emi; Sangai, Takafumi; Nishimura, Motoi; Matsushita, Kazuyuki; Hata, Akira; Nomura, Fumio; Inoue, Ituro

    2017-02-09

    Genetic testing for breast cancer predisposing genes, BRCA1 and BRCA2, can take advantage for early identification of carriers with pathogenic germline mutations. However, conventional approaches based on Sanger sequencing are laborious and expensive. Next-generation sequencing technology has a great impact on investigation of medical genomics and now applied clinical genetics. We provide a protocol based on a pool and capture method followed by high-throughput sequencing, which realizes a rapid, high-quality, high-accuracy and low-cost testing for mutations in BRCA1 and BRCA2 by using small amounts of input DNA. Custom capture probes were designed for 195 kb regions encompassing the entire BRCA1 and BRCA2. DNA libraries of 96 samples with distinct indices were pooled before hybridizing to the capture probes, which largely reduced labor and cost. The captured library was run on the Illumina MiSeq sequencer. We applied the method to 384 Japanese individuals including 11 patients with breast cancer whose mutation statuses had been determined by standard clinical testing and 373 individuals from a general population. 99.99% of coding exons and their 20 bp flanking regions were covered with a minimum of 20 reads and the average depth was 179.5, supporting confident variant detection. The sequencing method rendered concordant results for 11 patients with breast cancer compared with the standard clinical testing including nine mutations in eight patients. Among 373 individuals from the general population, novel stop gain and frameshift deletion in BRCA2 were identified, which led to truncated protein and were most likely to be pathogenic. The result suggests the importance of a large-scale population-wide screening for carriers of mutations in these genes.Journal of Human Genetics advance online publication, 9 February 2017; doi:10.1038/jhg.2017.5.

  15. Recurrent mutation testing of BRCA1 and BRCA2 in Asian breast cancer patients identify carriers in those with presumed low risk by family history.

    PubMed

    Kang, Peter Choon Eng; Phuah, Sze Yee; Sivanandan, Kavitta; Kang, In Nee; Thirthagiri, Eswary; Liu, Jian Jun; Hassan, Norhashimah; Yoon, Sook-Yee; Thong, Meow Keong; Hui, Miao; Hartman, Mikael; Yip, Cheng Har; Mohd Taib, Nur Aishah; Teo, Soo Hwang

    2014-04-01

    Although the breast cancer predisposition genes BRCA1 and BRCA2 were discovered more than 20 years ago, there remains a gap in the availability of genetic counselling and genetic testing in Asian countries because of cost, access and inaccurate reporting of family history of cancer. In order to improve access to testing, we developed a rapid test for recurrent mutations in our Asian populations. In this study, we designed a genotyping assay with 55 BRCA1 and 44 BRCA2 mutations previously identified in Asian studies, and validated this assay in 267 individuals who had previously been tested by full sequencing. We tested the prevalence of these mutations in additional breast cancer cases. Using this genotyping approach, we analysed recurrent mutations in 533 Malaysian breast cancer cases with <10 % a priori risk, and found 1 BRCA1 (0.2 %) and 5 BRCA2 (0.9 %) carriers. Testing in a hospital-based unselected cohort of 532 Singaporean breast cancer cases revealed 6 BRCA1 (1.1 %) and 3 BRCA2 (0.6 %) carriers. Overall, 2 recurrent BRCA1 and 1 BRCA2 mutations in Malays, 3 BRCA1 and 2 BRCA2 mutations in Chinese and 1 BRCA1 mutation in Indians account for 60, 24 and 20 % of carrier families, respectively. By contrast, haplotype analyses suggest that a recurrent BRCA2 mutation (c.262_263delCT) found in 5 unrelated Malay families has at least 3 distinct haplotypes. Taken together, our data suggests that panel testing may help to identify carriers, particularly Asian BRCA2 carriers, who do not present with a priori strong family history characteristics.

  16. Parental origin of mutation and the risk of breast cancer in a prospective study of women with a BRCA1 or BRCA2 mutation.

    PubMed

    Senst, N; Llacuachaqui, M; Lubinski, J; Lynch, H; Armel, S; Neuhausen, S; Ghadirian, P; Sun, P; Narod, S A

    2013-07-01

    The objective is to estimate the risk of breast cancer in women who carry a deleterious BRCA1 or BRCA2 mutation, according to parental origin of mutation. We conducted a cohort study of women with a BRCA1 mutation (n = 1523) or BRCA2 mutation (n = 369) who had not been diagnosed with breast or ovarian cancer. For each woman, the pedigree was reviewed and the origin of the mutation was assigned as probable paternal or maternal. The hazard ratio (HR) for developing breast cancer in the follow-up period was estimated for women with a paternal mutation compared to a maternal mutation. The risk of breast cancer was modestly higher in women with a paternal BRCA1 mutation compared to women with a maternal BRCA1 mutation (HR = 1.46; 95% CI = 0.99-2.16) but the difference was not significant (p = 0.06). The parental mutation origin did not affect the risk in women with a BRCA2 mutation. Our results are consistent with the hypothesis that there is an increased risk of breast cancer among women with a paternally inherited BRCA1 mutation compared to a maternally inherited mutation. However, the data are not sufficiently compelling to justify different screening recommendations for the two subgroups.

  17. Squamous Cell Carcinoma of the Pancreas in a Patient with Germline BRCA2 Mutation-Response to Neoadjuvant Radiochemotherapy

    PubMed Central

    Schultheis, Anne M.; Nguyen, Gia Phuong; Ortmann, Monika; Kruis, Wolfgang; Büttner, Reinhard; Schildhaus, Hans-Ulrich; Markiefka, Birgid

    2014-01-01

    Primary squamous cell carcinoma of the pancreas is a rare malignant neoplasia, accounting for approximately 0.5–2% of all malignant pancreatic tumors. These lesions are characterized by poor prognosis. Here we report on a case of a 57-year-old female patient with known BRCA2 germline mutation presenting with primary squamous cell carcinoma of the pancreas as the only malignancy. The tumor was locally advanced at the first presentation but responded almost completely to neoadjuvant radio-chemotherapy. Our case highlights the facts (i) that pancreatic carcinomas belong to the tumor spectrum of patients with the BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) and (ii) that tumors of the pancreas can represent the first or even the only manifestation of HBOC. Furthermore, this case of a nonkeratinizing squamous cell carcinoma indicates that HBOC-associated carcinomas of the pancreas might be characterized by a broader morphological spectrum than was previously thought. Since BRCA mutations cause deficiency of DNA double-strand breakage repair in tumors, neoadjuvant treatment regimens might become a reasonable option in HBOC-associated pancreatic carcinomas. To our knowledge, this is the first reported case of a primary pancreatic squamous cell carcinoma in a patient with this particular genetic background of BRCA2-associated HBOC. PMID:24959366

  18. Use of Risk-Reducing Surgeries in a Prospective Cohort of 1,499 BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Chai, Xinglei; Friebel, Tara M.; Singer, Christian F.; Evans, D. Gareth; Lynch, Henry T.; Isaacs, Claudine; Garber, Judy E.; Neuhausen, Susan L.; Matloff, Ellen; Eeles, Rosalind; Tung, Nadine; Weitzel, Jeffrey N.; Couch, Fergus J.; Hulick, Peter J.; Ganz, Patricia A.; Daly, Mary B.; Olopade, Olufunmilayo I.; Tomlinson, Gail; Blum, Joanne L.; Domchek, Susan M.; Chen, Jinbo; Rebecck, Timothy R.

    2014-01-01

    Purpose Inherited mutations in BRCA1 or BRCA2 (BRCA1/2) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. Methods We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited BRCA1/2 mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM, and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan-Meier analyses. Results Use of RRSO was 45% for BRCA1 and 34% for BRCA2 by age 40, and 86% for BRCA1 and 71% for BRCA2 by age 50. RRM usage was estimated to be 46% by age 70 in both BRCA1 and BRCA2 carriers. BRCA1 mutation carriers used RRSO more frequently than BRCA2 mutation carriers overall, but the uptake of RRSO in BRCA2 was similar after mutation testing and in women born since 1960. RRM uptake was similar for both BRCA1 and BRCA2. Childbearing influenced use of RRSO and RRM in both BRCA1 and BRCA2. Conclusions Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO. PMID:25311111

  19. Molecular insights into the OGG1 gene, a cancer risk modifier in BRCA1 and BRCA2 mutations carriers

    PubMed Central

    Benitez-Buelga, Carlos; Vaclová, Tereza; Ferreira, Sofia; Urioste, Miguel; Inglada-Perez, Lucia; Soberón, Nora; Blasco, Maria A.; Osorio, Ana; Benitez, Javier

    2016-01-01

    We have recently shown that rs2304277 variant in the OGG1 glycosidase gene of the Base Excision Repair pathway can increase ovarian cancer risk in BRCA1 mutation carriers. In the present study, we aimed to explore the role of this genetic variant on different genome instability hallmarks to explain its association with cancer risk. We have evaluated the effect of this polymorphism on OGG1 transcriptional regulation and its contribution to telomere shortening and DNA damage accumulation. For that, we have used a series of 89 BRCA1 and BRCA2 mutation carriers, 74 BRCAX cases, 60 non-carrier controls and 23 lymphoblastoid cell lines (LCL) derived from BRCA1 mutation carriers and non-carriers. We have identified that this SNP is associated to a significant OGG1 transcriptional down regulation independently of the BRCA mutational status and that the variant may exert a synergistic effect together with BRCA1 or BRCA2 mutations on DNA damage and telomere shortening. These results suggest that this variant, could be associated to a higher cancer risk in BRCA1 mutation carriers, due to an OGG1 transcriptional down regulation and its effect on genome instability. PMID:27015555

  20. Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers

    PubMed Central

    Stevens, Kristen N.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Greene, Mark H.; Andrulis, Irene L.; Thomassen, Mads; Caligo, Maria; Nathanson, Katherine L.; Jakubowska, Anna; Osorio, Ana; Hamann, Ute; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Southey, Melissa; Buys, Saundra S.; Singer, Christian F.; Hansen, Thomas V.O.; Arason, Adalgeir; Offit, Kenneth; Piedmonte, Marion; Montagna, Marco; Imyanitov, Evgeny; Tihomirova, Laima; Sucheston, Lara; Beattie, Mary; Neuhausen, Susan L.; Szabo, Csilla I.; Simard, Jacques; Spurdle, Amanda B.; Healey, Sue; Chen, Xiaoqing; Rebbeck, Timothy R.; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C; Couch, Fergus J.

    2012-01-01

    Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [Hazard ratio (HR)=1.55, 95% CI 1.25–1.92, p=6.0×10−5]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers [HR=1.09, 95% CI 0.96–1.24, p=0.18]. No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations. PMID:23011509

  1. Ovarian Cancer Susceptibility Alleles and Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Ramus, Susan J.; Antoniou, Antonis C; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E.; Aalfs, Cora M.; Meijers-Heijboer, Hanne E.J.; van Asperen, Christi J.; van Roozendaal, K.E.P.; Hoogerbrugge, Nicoline; Collée, J. Margriet; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Pathak, Harsh; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K.; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; Van Le, Linda; Hoffman, James S; Toland, Amanda Ewart; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Olah, Edith; Vaszko, Tibor; Teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M; van Rensburg, Elizabeth J; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V. Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D.P.; Gayther, Simon A.; Simard, Jacques; Easton, Douglas F.; Couch, Fergus J.; Chenevix-Trench, Georgia

    2012-01-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67–0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21–1.83) P-trend = 1.8 × 10−4, rs717852 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.6 × 10−4, rs9303542 HR = 1.16 (95% CI: 1.02–1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81–0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.1 × 10−4. The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer. PMID:22253144

  2. Reproductive factors and breast cancer risk among BRCA1 or BRCA2 mutation carriers: results from ten studies.

    PubMed

    Pan, Hong; He, Zhongyuan; Ling, Lijun; Ding, Qiang; Chen, Lin; Zha, Xiaoming; Zhou, Wenbin; Liu, Xiaoan; Wang, Shui

    2014-02-01

    Although reproductive factors are among the most well-established risk factors for breast cancer in the general population, it is still a matter for debate whether these factors act as risk modifiers among BRCA1 or BRCA2 mutation carriers. This meta-analysis is the first to be performed to determine the relationship between reproductive factors and breast cancer risk among BRCA1 and BRCA2 mutation carriers. We searched the PubMed database up to February 2013. A total of ten studies met the inclusion criteria. The results showed that the reproductive factors may be associated with breast cancer risk only among BRCA1 mutation carriers. No association was found between parity and breast cancer risk. Compared with women at the youngest age in the first-birth category, women in the oldest age category were at a 38% lower risk of breast cancer (RR=0.62, 95%CI=0.45-0.85). Breastfeeding for at least 1 or 2 years was associated with a 37% reduction in breast cancer risk (RR=0.63, 95%CI=0.46-0.86). Women at the oldest age in the menarche category were at a 34% lower risk of breast cancer (RR=0.66, 95%CI=0.53-0.81) than women in the youngest age category. However, none of the reproductive factors were associated with breast cancer risk among BRCA2 mutation carriers. In conclusion, late age at first birth, breastfeeding, and late age at menarche protect against breast cancer in BRCA1 mutation carriers only. Further studies are needed to explore the mechanisms.

  3. Low prevalence of BRCA1 and BRCA2 mutations in the sporadic breast cancer of Spanish population.

    PubMed

    de Juan Jiménez, Inmaculada; Esteban Cardeñosa, Eva; Palanca Suela, Sarai; Barragán González, Eva; Aznar Carretero, Ismael; Munárriz Gandía, Blanca; Santaballa Bertran, Ana; Torregrosa Maicas, María Dolores; Guillén Ponce, Carmen; Sánchez Heras, Ana Beatriz; Bayón Lara, Ana; Fuster Lluch, Oscar; Bolufer Gilabert, Pascual

    2012-03-01

    The true prevalence of BRCA1/BRCA2 (BRCAs) germline mutations in sporadic breast or ovarian cancer (SBC/SOC) in Caucasian population is not well established. The aim of the study is to establish the prevalence of BRCAs mutations in SBC to ponder its relevance in the programs of genetic counseling in cancer and to explore the genotype-phenotype relationship of these particular breast cancers. The study was performed in 495 SBC. We sought 46 BRCA1 and 53 BRCA2 pathogenic mutations reported in the Spanish population. We followed a high resolution melting method performed in the LightCycler 480 (Roche Diagnostics) for the screening of these Spanish mutations using 49 primer pairs. Eight different deleterious mutations, one of them novel, were detected in nine patients, five without family history of BC/OC, what yields a true prevalence of 1.05% for BRCAs mutations in SBC. Furthermore, we found 18 unknown variants. Larger tumour size (T > 1) and earlier presentation are the independent parameters associated with the presence of BRCAs pathogenic mutations in SBC (P < 0.01) and the BRCA1 mutations carriers develop steroid-receptors negative tumors. Our results indicate that the true prevalence of BRCAs germline deleterious mutations in SBC of Spaniards is low. However, this does not lessens its relevance since the presence of BRCAs mutations in SBC could represent circa 16% of total BRCAs mutations detected in BC. SBCs of BRCAs mutation carriers have phenotype more aggressiveness than SBC without BRCAs mutation.

  4. An Exploratory Study to Determine Whether BRCA1 and BRCA2 Mutation Carriers Have Higher Risk of Cardiac Toxicity

    PubMed Central

    Sajjad, Monique; Fradley, Michael; Sun, Weihong; Kim, Jongphil; Zhao, Xiuhua; Pal, Tuya; Ismail-Khan, Roohi

    2017-01-01

    Anthracycline-based cardiotoxicity is concerning for women with breast cancer and portends a dose-dependent risk of developing left ventricular dysfunction. Overall, the prevalence of heart failure (HF) is ≈2% of the total US population; however, BRCA-deficient mice have shown increased HF. We evaluated for the inherent risk of HF in women with BRCA mutations to determine whether treatment with anthracycline-based therapy increased this risk. We obtained results on BRCA mutation carriers regarding cancer treatment and HF, identified through the BRCA patient advocacy organization Facing Our Risk for Cancer Empowered (FORCE) and the Moffitt-based Inherited Cancer Registry. In our patient group (232 BRCA1 and 159 BRCA2 patients; 10 with both mutations), 7.7% reported HF, with similar proportions in BRCA1 versus BRCA2 carriers (7.4% and 8.2%, respectively). These proportions are significantly higher than published rates (p < 0.001). There was no statistically significant difference in HF rates comparing anthracycline-treated versus anthracycline-naïve patients however (7.1% vs. 8.3%; p = 0.67). In addition, 9.1% of BRCA1 carriers and 8.2% of BRCA2 carriers reported arrhythmias. BRCA mutation carriers showed increased risk of cardiotoxicity versus the general population and an overall increased risk of cardiotoxicity from anthracycline-based therapy. Our study supports data that BRCA carriers have increased non-cancer mortality from cardiotoxicity. A prospective trial to determine HF and conduction abnormalities in this population is warranted. PMID:28157161

  5. Altered BRCA1 and BRCA2 responses and mutation of BRCA1 gene in mice exposed chronically and transgenerationally to aqueous extract of betel nut (AEBN).

    PubMed

    Choudhury, Yashmin; Sharan, Rajeshwar N

    2011-01-01

    The Brca1 and Brca2 tumor suppressor genes are involved in the maintenance of genomic integrity as they facilitate error free DNA repair. This study was designed to understand the role of Brca1 and Brca2 in betel nut (BN) induced chronic and transgenerational carcinogenesis in mice. Young male and female Swiss Albino mice were chronically as well as transgenerationally exposed to aqueous extract of betel nut (AEBN) in drinking water (2 mg ml(-1)) for up to 24 weeks. In chronically exposed mice, the levels of Brca1 and Brca2 proteins were elevated to approximately 1.4-fold over the age matched controls after 2 weeks of exposure to AEBN, followed by a decline below the controls. In transgenerationally exposed mice, both Brca1 and Brca2 proteins remained below the controls from the onset of AEBN exposure and rapidly declined further, indicating a loss of tumor suppressor protection. Nucleotide sequencing of exon 11 of Brca1 and exon 27 of Brca2 did not reveal mutation in liver nodules of chronically exposed mice, while a G → C mutation Brca1 was observed in liver nodules as well as in solid tumors developing in transgenerationally exposed mice. Thus, the genomic instability arising due to the lowering in the levels of Brca1 and Brca2 proteins and mutation in exon 11 of Brca1 gene contributed to the increased risk of cancer in mice exposed transgenerationally to AEBN.

  6. Spontaneous and irradiation-induced tumor susceptibility in BRCA2 germline mutant mice and cooperative effects with a p53 germline mutation.

    PubMed

    McAllister, Kimberly A; Houle, Christopher D; Malphurs, Jason; Ward, Toni; Collins, N Keith; Gersch, William; Wharey, Laura; Seely, John C; Betz, Laura; Bennett, L Michelle; Wiseman, Roger W; Davis, Barbara J

    2006-01-01

    Mutations in both p53 and BRCA2 are commonly seen together in human tumors suggesting that the loss of both genes enhances tumor development. To elucidate this interaction in an animal model, mice lacking the carboxy terminal domain of Brca2 were crossed with p53 heterozygous mice. Females from this intercross were then irradiated with an acute dose of 5 Gy ionizing radiation at 5 weeks of age and compared to nonirradiated controls. We found decreased survival and timing of tumor onsets, and significantly higher overall tumor incidences and prevalence of particular tumors, including stomach tumors and squamous cell carcinomas, associated with the homozygous loss of Brca2, independent of p53 status. The addition of a p53 mutation had a further impact on overall survival, incidence of osteosarcomas and stomach tumors, and tumor latency. The spectrum of tumors observed for this Brca2 germline mouse model suggest that it faithfully recapitulates some human disease phenotypes associated with BRCA2 loss. In addition, these findings include extensive in vivo data demonstrating that germline Brca2 and p53 mutations cooperatively affect animal survivals, tumor susceptibilities, and tumor onsets.

  7. Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations

    PubMed Central

    Phillips, Kelly-Anne; Collins, Ian M.; Milne, Roger L.; McLachlan, Sue Anne; Friedlander, Michael; Hickey, Martha; Stern, Catharyn; Hopper, John L.; Fisher, Richard; Kannemeyer, Gordon; Picken, Sandra; Smith, Charmaine D.; Kelsey, Thomas W.; Anderson, Richard A.

    2016-01-01

    STUDY QUESTION Do women with BRCA1 or BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration? SUMMARY ANSWER Women with a germline mutation in BRCA1 have reduced ovarian reserve as measured by AMH. WHAT IS KNOWN ALREADY The DNA repair enzymes encoded by BRCA1 and BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan. STUDY DESIGN, SIZE, DURATION This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible women were from families segregating BRCA1 or BRCA2 mutations and had known mutation status. Participants were aged 25–45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking. MAIN RESULTS AND THE ROLE OF CHANCE Mean AMH concentration was negatively associated with age (P < 0.001). Mutation carriers were younger at blood draw than non-carriers (P ≤ 0.031). BRCA1 mutation carriers had, on average, 25% (95% CI: 5%–41%, P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11–303, P = 0

  8. BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age

    PubMed Central

    Bergthorsson, J; Ejlertsen, B; Olsen, J; Borg, A; Nielsen, K; Barkardottir, R; Klausen, S; Mouridsen, H; Winther, K; Fenger, K; Niebuhr, A; Harboe, T; Niebuhr, E

    2001-01-01

    INTRODUCTION—A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carriers frequently have a positive family history of breast and ovarian cancer, are often diagnosed at a young age, and may have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general.
OBJECTIVES—To estimate the prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish patients affected with bilateral or multifocal breast cancer and to determine the relationship of mutation status to family history of cancer.
SUBJECTS—From the files of the Danish Breast Cancer Cooperative Group (DBCG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) disease.
METHODS—DNA from the subjects was screened for BRCA1 and BRCA2 mutations using single strand conformation analysis (SSCA) and the protein truncation test (PTT). Observed and expected cancer incidence in first degree relatives of the patients was estimated using data from the Danish Cancer Registry.
RESULTS—Twenty four mutation carriers were identified (20%), of whom 13 had a BRCA1 mutation and 11 carried a BRCA2 mutation. Two mutations in BRCA1 were found repeatedly in the material and accounted for seven of the 24 (29%) mutation carriers. The mutation frequency was about equal in patients with bilateral (22%) and multifocal breast cancer (18%). The incidence of breast and ovarian cancer was greatly increased in first degree relatives of BRCA1 and BRCA2 mutation carriers, but to a much lesser degree in relatives of non-carriers. An increased risk of cancer was also noted in brothers of non-carriers.
CONCLUSIONS—A relatively broad spectrum of germline mutations was observed in BRCA1 and BRCA2 and most of the mutations are present in other populations. Our results indicate that a diagnosis of bilateral and multifocal breast

  9. Double PALB2 and BRCA1/BRCA2 mutation carriers are rare in breast cancer and breast-ovarian cancer syndrome families from the French Canadian founder population

    PubMed Central

    ANCOT, FRÉDÉRIC; ARCAND, SUZANNA L.; MES-MASSON, ANNE-MARIE; PROVENCHER, DIANE M.; TONIN, PATRICIA N.

    2015-01-01

    French Canadian families with breast cancer and breast-ovarian cancer syndrome harbor specific BRCA1, BRCA2 and PALB2 germline mutations, which have been attributed to common founders. Mutations in these genes confer an increased risk to breast and ovarian cancers, and have been identified to play a role in and directly interact with the common homologous recombination DNA repair pathways. Our previous study described the case of a female diagnosed with breast cancer at 45 years old, who harbored the PALB2:c.2323C>T [p.Q775X] and BRCA2:c.9004G>A [p.E3002K] germline mutations, which have been found to recur in the French Canadian cancer families. As the frequency of double heterozygous carriers of breast-ovarian cancer susceptibility alleles is unknown, and due to the possibility that there may be implications for genetic counseling and management for these carriers, the present study investigated the co-occurrence of BRCA1/BRCA2 and PALB2 mutations in the French Canadian cancer families. The PALB2:c.2323C>T [p.Q775X] mutation, which is the only PALB2 mutation to have been identified in French Canadian cancer families, was screened in 214 breast cancer cases and 22 breast-ovarian cancer cases from 114 BRCA1/BRCA2 mutation-positive French Canadian breast cancer (n=61) and breast-ovarian cancer (n=53) families using a tailored polymerase chain reaction-based TaqMan® SNP Genotyping Assay. No additional PALB2:c.2323C>T [p.Q775X] mutation carriers were identified among the BRCA1/BRCA2 mutation carriers. The results suggest that carriers of the PALB2:c.2323C>T [p.Q775X] mutation rarely co-occur in French Canadian breast cancer and breast-ovarian cancer families harboring BRCA1 or BRCA2 mutations. PMID:26137147

  10. Double PALB2 and BRCA1/BRCA2 mutation carriers are rare in breast cancer and breast-ovarian cancer syndrome families from the French Canadian founder population.

    PubMed

    Ancot, Frédéric; Arcand, Suzanna L; Mes-Masson, Anne-Marie; Provencher, Diane M; Tonin, Patricia N

    2015-06-01

    French Canadian families with breast cancer and breast-ovarian cancer syndrome harbor specific BRCA1, BRCA2 and PALB2 germline mutations, which have been attributed to common founders. Mutations in these genes confer an increased risk to breast and ovarian cancers, and have been identified to play a role in and directly interact with the common homologous recombination DNA repair pathways. Our previous study described the case of a female diagnosed with breast cancer at 45 years old, who harbored the PALB2:c.2323C>T [p.Q775X] and BRCA2:c.9004G>A [p.E3002K] germline mutations, which have been found to recur in the French Canadian cancer families. As the frequency of double heterozygous carriers of breast-ovarian cancer susceptibility alleles is unknown, and due to the possibility that there may be implications for genetic counseling and management for these carriers, the present study investigated the co-occurrence of BRCA1/BRCA2 and PALB2 mutations in the French Canadian cancer families. The PALB2:c.2323C>T [p.Q775X] mutation, which is the only PALB2 mutation to have been identified in French Canadian cancer families, was screened in 214 breast cancer cases and 22 breast-ovarian cancer cases from 114 BRCA1/BRCA2 mutation-positive French Canadian breast cancer (n=61) and breast-ovarian cancer (n=53) families using a tailored polymerase chain reaction-based TaqMan® SNP Genotyping Assay. No additional PALB2:c.2323C>T [p.Q775X] mutation carriers were identified among the BRCA1/BRCA2 mutation carriers. The results suggest that carriers of the PALB2:c.2323C>T [p.Q775X] mutation rarely co-occur in French Canadian breast cancer and breast-ovarian cancer families harboring BRCA1 or BRCA2 mutations.

  11. Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Gronwald, Jacek; Robidoux, Andre; Kim-Sing, Charmaine; Tung, Nadine; Lynch, Henry T; Foulkes, William D; Manoukian, Siranoush; Ainsworth, Peter; Neuhausen, Susan L; Demsky, Rochelle; Eisen, Andrea; Singer, Christian F; Saal, Howard; Senter, Leigha; Eng, Charis; Weitzel, Jeffrey; Moller, Pal; Gilchrist, Dawna M; Olopade, Olufunmilayo; Ginsburg, Ophira; Sun, Ping; Huzarski, Tomasz; Lubinski, Jan; Narod, Steven A

    2014-07-01

    Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20-0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1-4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44-1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment.

  12. Modeling Impact of BRCA1 and BRCA2 Mutations in Mammary Epithelial Cells

    DTIC Science & Technology

    2012-09-01

    mastectomy , and have now collected a total of 16 samples. Epithelial cell isolation and immortalization is underway – we have one verified BRCA2...breast cancer burden in the US [1]. Prophylactic mastectomy , in concert with increased mammographic surveillance, remains the standard of care for BRCA1...lines, called MCK cells, from women opting for prophylactic mastectomy . These lines have been isolated from pre-neoplastic breast tissue that is not

  13. Prospective evaluation of alcohol consumption and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Cybulski, Cezary; Lubinski, Jan; Huzarski, Tomasz; Lynch, Henry T; Randall, Susan Armel; Neuhausen, Susan L; Senter, Leigha; Friedman, Susan; Ainsworth, Peter; Singer, Christian; Foulkes, William D; Narod, Steven A; Sun, Ping; Kotsopoulos, Joanne

    2015-06-01

    Given the adverse effect of alcohol in the development of breast cancer among women in the general population, we evaluated whether a similar association exists among women with a BRCA1 or BRCA2 mutation. Information regarding baseline daily alcohol consumption was abstracted from a research questionnaire for 3067 BRCA mutation carriers enrolled in a prospective cohort study. Women were followed biennially until the date of the last follow-up questionnaire, date of breast cancer diagnosis, date of prophylactic bilateral mastectomy, or date of death. Cox proportional hazards models were used to estimate relative risks (RRs) and 95 % confidence intervals (CIs) for invasive breast cancer associated with alcohol consumed at or prior to completion of the baseline questionnaire. After a mean of 5.4 years of follow-up, we observed 259 incident cases of primary invasive breast cancer. Compared with non-users, the adjusted RRs were 1.06 (95 % CI 0.78-1.44) for ever use and 1.08 (0.79-1.47) for current alcohol use. For women in the highest versus lowest quintile of cumulative alcohol consumption, the RR was 0.94 (95 % CI 0.63-1.40; P trend = 0.65). Our findings suggest that alcohol consumption is not a risk factor for breast cancer among women with a BRCA1 or BRCA2 mutation.

  14. Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry

    PubMed Central

    Paula, André E.; Pereira, Rui; Andrade, Carlos E.; Felicio, Paula S.; Souza, Cristiano P.; Mendes, Deise R.P.; Volc, Sahlua; Berardinelli, Gustavo N.; Grasel, Rebeca S.; Sabato, Cristina S.; Viana, Danilo V.; Machado, José Carlos; Costa, José Luis; Mauad, Edmundo C.; Scapulatempo-Neto, Cristovam; Arun, Banu; Reis, Rui M.; Palmero, Edenir I.

    2016-01-01

    Background There are very few data about the mutational profile of families at-risk for hereditary breast and ovarian cancer (HBOC) from Latin America (LA) and especially from Brazil, the largest and most populated country in LA. Results Of the 349 probands analyzed, 21.5% were BRCA1/BRCA2 mutated, 65.3% at BRCA1 and 34.7% at BRCA2 gene. The mutation c.5266dupC (former 5382insC) was the most frequent alteration, representing 36.7% of the BRCA1 mutations and 24.0% of all mutations identified. Together with the BRCA1 c.3331_3334delCAAG mutation, these mutations constitutes about 35% of the identified mutations and more than 50% of the BRCA1 pathogenic mutations. Interestingly, six new mutations were identified. Additionally, 39 out of the 44 pathogenic mutations identified were not previously reported in the Brazilian population. Besides, 36 different variants of unknown significance (VUS) were identified. Regarding ancestry, average ancestry proportions were 70.6% European, 14.5% African, 8.0% Native American and 6.8% East Asian. Materials and methods This study characterized 349 Brazilian families at-risk for HBOC regarding their germline BRCA1/BRCA2 status and genetic ancestry. Conclusions This is the largest report of BRCA1/BRCA2 assessment in an at-risk HBOC Brazilian population. We identified 21.5% of patients harboring BRCA1/BRCA2 mutations and characterized the genetic ancestry of a sample group at-risk for hereditary breast cancer showing once again how admixed is the Brazilian population. No association was found between genetic ancestry and mutational status. The knowledge of the mutational profile in a population can contribute to the definition of more cost-effective strategies for the identification of HBOC families. PMID:27741520

  15. Factors Influencing Ovulation and the Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Kotsopoulos, Joanne; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Demsky, Rochelle; Neuhausen, Susan L.; Kim-Sing, Charmaine; Tung, Nadine; Friedman, Susan; Senter, Leigha; Weitzel, Jeffrey; Karlan, Beth; Moller, Pal; Sun, Ping; Narod, Steven A.

    2015-01-01

    The role of the lifetime number of ovulatory cycles has not been evaluated in the context of BRCA – associated ovarian cancer. Thus, we conducted a matched case-control study to evaluate the relationship between the cumulative number of ovulatory cycles (and contributing components) and risk of developing ovarian cancer in BRCA mutation carriers (1,329 cases and 5,267 controls). Information regarding reproductive and hormonal factors was collected from a routinely administered questionnaire. Conditional logistic regression was used to evaluate all associations. We observed a 45% reduction in the risk of developing ovarian cancer among women in the lowest vs. highest quartile of ovulatory cycles (OR = 0.55; 95%CI 0.41–0.75 P=0.0001). Breastfeeding for more than 12 months was associated with a 38% (95%CI 0.48–0.79) and 50% (95%CI 0.29–0.84) reduction in risk among BRCA1 and BRCA2 mutation carriers, respectively. For oral contraceptive use, maximum benefit was seen with five or more years of use among BRCA1 mutation carriers (OR = 0.50; 95%CI 0.40–0.63) and three or more years for BRCA2 mutation carriers (OR = 0.42; 95%CI 0.22–0.83). Increasing parity was associated with a significant inverse trend among BRCA1 (OR = 0.87; 95%CI 0.79–0.96; P-trend=0.005) but not BRCA2 mutation carriers (OR 0.98; 95%CI 0.81–1.19; P-trend=0.85). A later age at menopause was associated with an increased risk in women with a BRCA1 mutation (OR trend = 1.18; 95%CI 1.03–1.35; P =0.02). These findings support an important role of breastfeeding and oral contraceptive use for the primary prevention of ovarian cancer among women carrying BRCA mutations. PMID:25482078

  16. Comprehensive analysis of BRCA1 and BRCA2 germline mutations in a large cohort of 5931 Chinese women with breast cancer.

    PubMed

    Zhang, Juan; Sun, Jie; Chen, Jiuan; Yao, Lu; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

    2016-08-01

    We determined the prevalence and characteristics of BRCA1/2 germline mutations in a large cohort of Chinese women with breast cancer. A total of 5931 unselected Chinese women with breast cancer were enrolled in this study and underwent testing for BRCA1/2 mutations. Of these, 543 patients were familial breast cancer, 1033 were early-onset disease (≤40 years) without family history of breast cancer, and 4355 were sporadic breast cancer. In total, 232 patients (3.9 %) carried a BRCA1 or BRCA2 mutation (110 in BRCA1and 122 in BRCA2) in this cohort of 5931 patients. BRCA1/2 mutation rate was 16.9 % (92/543) in familial breast cancers, 5.2 % (54/1033) in early-onset breast cancers (≤40 years), and 2.0 % in sporadic breast cancers (>40 years), respectively. The BRCA1/2 mutation rate was 27.0 % in 111 familial breast cancers diagnosed at and before the age of 40. 41.4 % of mutations in this cohort were specific for Chinese population. Recurrent mutations accounted for 44.8 % of the entire mutations in 2382 cases that BRCA1 and BRCA2 genes were fully sequenced in this study. Both BRCA1 and BRCA2 mutation carriers were significantly more likely to be early-onset and bilateral breast cancers, high-grade cancer, and to have a family history of breast cancer compared with non-carriers. BRCA1 mutation carriers were more likely to be triple-negative cancer than BRCA2 mutation carriers and non-carriers. Our data provide guidelines for Chinese women with breast cancer who should undergo BRCA1/2 genetic testing; additionally, recurrent mutations account for nearly half of the mutations and some of them are specific for Chinese women.

  17. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study.

    PubMed

    de Juan, Inmaculada; Palanca, Sarai; Domenech, Asunción; Feliubadaló, Lidia; Segura, Ángel; Osorio, Ana; Chirivella, Isabel; de la Hoya, Miguel; Sánchez, Ana Beatriz; Infante, Mar; Tena, Isabel; Díez, Orland; Garcia-Casado, Zaida; Vega, Ana; Teulé, Àlex; Barroso, Alicia; Pérez, Pedro; Durán, Mercedes; Carrasco, Estela; Juan-Fita, M José; Murria, Rosa; Llop, Marta; Barragan, Eva; Izquierdo, Ángel; Benítez, Javier; Caldés, Trinidad; Salas, Dolores; Bolufer, Pascual

    2015-12-01

    Male breast cancer (MBC) is a rare disease that represents <1% of all breast cancers (BCs). We analyze the results of a multicenter study performed in Spanish familial MBC including family history of hereditary breast and ovarian cancer syndrome (HBOCS) and clinicopathological features. We also study the relationship between BRCA1/BRCA2 mutational status in male relatives affected with cancer (MAC) and, family history and tumor types. The study included 312 men index cases with family history of HBOCS and 61 MAC BRCA1/2 mutation-carriers. Family history, histological grade (HG), clinicopathological and immunohistochemistry data were collected. BRCA1/2 mutation analyses were performed by direct sequencing or screening methods and the large rearrangements by multiplex ligation dependent probe amplification. We found 49 mutation-carriers (15.7%), 95.9% with BRCA2 mutations. BRCA2 mutation-carriers were associated with families with at least one MBC and one BC in female (type II; p = 0.05). Strong association were found between the presence of pathogenic mutations in MBCs and the advanced HG (p = 0.003). c.658_659delTG, c.2808_2811delACAA, c.6275_6276delTT and c.9026_9030delATCAT were the most prevalent mutations. In 61 MAC we found 20 mutations in BRCA1 and 41 in BRCA2. For MAC we show that mutational status was differentially associated with family history (p = 0.018) and tumor type, being BRCA2 mutations linked with BC and prostatic cancer (p = 0.018). MBC caused by BRCA1/2 mutations define two types of MBCs. The most frequent caused by BRCA2 mutation linked to type II families and the rarest one attributed to BRCA1 mutation. Tumor associated with MAC suggest that only BRCA2 mutations have to do with a specific type of cancer (BC and prostatic cancer); but the linkage to tumors is questionable for BRCA1 mutations .

  18. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers.

    PubMed

    Antoniou, Antonis C; Sinilnikova, Olga M; McGuffog, Lesley; Healey, Sue; Nevanlinna, Heli; Heikkinen, Tuomas; Simard, Jacques; Spurdle, Amanda B; Beesley, Jonathan; Chen, Xiaoqing; Neuhausen, Susan L; Ding, Yuan C; Couch, Fergus J; Wang, Xianshu; Fredericksen, Zachary; Peterlongo, Paolo; Peissel, Bernard; Bonanni, Bernardo; Viel, Alessandra; Bernard, Loris; Radice, Paolo; Szabo, Csilla I; Foretova, Lenka; Zikan, Michal; Claes, Kathleen; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L; Ozcelik, Hilmi; Glendon, Gord; Gerdes, Anne-Marie; Thomassen, Mads; Sunde, Lone; Caligo, Maria A; Laitman, Yael; Kontorovich, Tair; Cohen, Shimrit; Kaufman, Bella; Dagan, Efrat; Baruch, Ruth Gershoni; Friedman, Eitan; Harbst, Katja; Barbany-Bustinza, Gisela; Rantala, Johanna; Ehrencrona, Hans; Karlsson, Per; Domchek, Susan M; Nathanson, Katherine L; Osorio, Ana; Blanco, Ignacio; Lasa, Adriana; Benítez, Javier; Hamann, Ute; Hogervorst, Frans B L; Rookus, Matti A; Collee, J Margriet; Devilee, Peter; Ligtenberg, Marjolijn J; van der Luijt, Rob B; Aalfs, Cora M; Waisfisz, Quinten; Wijnen, Juul; van Roozendaal, Cornelis E P; Peock, Susan; Cook, Margaret; Frost, Debra; Oliver, Clare; Platte, Radka; Evans, D Gareth; Lalloo, Fiona; Eeles, Rosalind; Izatt, Louise; Davidson, Rosemarie; Chu, Carol; Eccles, Diana; Cole, Trevor; Hodgson, Shirley; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; Buecher, Bruno; Léoné, Mélanie; Bressac-de Paillerets, Brigitte; Remenieras, Audrey; Caron, Olivier; Lenoir, Gilbert M; Sevenet, Nicolas; Longy, Michel; Ferrer, Sandra Fert; Prieur, Fabienne; Goldgar, David; Miron, Alexander; John, Esther M; Buys, Saundra S; Daly, Mary B; Hopper, John L; Terry, Mary Beth; Yassin, Yosuf; Singer, Christian; Gschwantler-Kaulich, Daphne; Staudigl, Christine; Hansen, Thomas v O; Barkardottir, Rosa Bjork; Kirchhoff, Tomas; Pal, Prodipto; Kosarin, Kristi; Offit, Kenneth; Piedmonte, Marion; Rodriguez, Gustavo C; Wakeley, Katie; Boggess, John F; Basil, Jack; Schwartz, Peter E; Blank, Stephanie V; Toland, Amanda E; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny N; Allavena, Anna; Schmutzler, Rita K; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Deissler, Helmut; Fiebig, Britta; Suttner, Christian; Schönbuchner, Ines; Gadzicki, Dorothea; Caldes, Trinidad; de la Hoya, Miguel; Pooley, Karen A; Easton, Douglas F; Chenevix-Trench, Georgia

    2009-11-15

    Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

  19. A non-synonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

    PubMed Central

    Ding, Yuan C.; McGuffog, Lesley; Healey, Sue; Friedman, Eitan; Laitman, Yael; Shani-Shimon–Paluch; Kaufman, Bella; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Gronwald, Jacek; Huzarski, Tomasz; Cybulski, Cezary; Byrski, Tomasz; Osorio, Ana; Cajal, Teresa Ramóny; Stavropoulou, Alexandra V; Benítez, Javier; Hamann, Ute; Rookus, Matti; Aalfs, Cora M.; de Lange, Judith L.; Meijers-Heijboer, Hanne E.J.; Oosterwijk, Jan C.; van Asperen, Christi J.; García, Encarna B. Gómez; Hoogerbrugge, Nicoline; Jager, Agnes; van der Luijt, Rob B.; Easton, Douglas F.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Tischkowitz, Marc; Godwin, Andrew K.; Pathak, Harsh; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Barjhoux, Laure; Léoné, Mélanie; Gauthier-Villars, Marion; Caux-Moncoutier, Virginie; de Pauw, Antoine; Hardouin, Agnès; Berthet, Pascaline; Dreyfus, Hélène; Ferrer, Sandra Fert; Collonge-Rame, Marie-Agnès; Sokolowska, Johanna; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Maria, Muy-Kheng Tea; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Sarrel, Kara; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion R; Andrews, Lesley; Cohn, David; DeMars, Leslie R.; DiSilvestro, Paul; Rodriguez, Gustavo; Toland, Amanda Ewart; Montagna, Marco; Agata, Simona; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Ramus, Susan J; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Ganz, Patricia A.; Beattie, Mary S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Arnold, Norbert; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Nevanlinna, Heli; Aittomäki, Kristiina; Simard, Jacques; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Tomlinson, Gail E.; Weitzel, Jeffrey; Garber, Judy E.; Olopade, Olufunmilayo I.; Rubinstein, Wendy S.; Tung, Nadine; Blum, Joanne L.; Narod, Steven A.; Brummel, Sean; Gillen, Daniel L.; Lindor, Noralane; Fredericksen, Zachary; Pankratz, Vernon S.; Couch, Fergus J.; Radice, Paolo; Peterlongo, Paolo; Greene, Mark H.; Loud, Jennifer T.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Gerdes, Anne-Marie; Thomassen, Mads; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Lee, Andrew; Chenevix-Trench, Georgia; Antoniou, Antonis C; Neuhausen, Susan L.

    2012-01-01

    Background We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 [Hazard ratio (HR) = 1.43; 95% CI: 1.06–1.92; p = 0.019] and BRCA2 mutation carriers (HR=2.21; 95% CI: 1.39–3.52, p=0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class 2 mutations than class 1 (mutations (class 2 HR=1.86, 95% CI: 1.28–2.70; class 1 HR=0.86, 95%CI:0.69–1.09; p-for difference=0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (HR = 2.42; p = 0.03). Conclusion The IRS1 Gly972Arg SNP, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class 2 mutation carriers. Impact These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. PMID:22729394

  20. BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland.

    PubMed

    Ratajska, Magdalena; Brozek, Izabela; Senkus-Konefka, Elzbieta; Jassem, Jacek; Stepnowska, Magdalena; Palomba, Grazia; Pisano, Marina; Casula, Milena; Palmieri, Giuseppe; Borg, Ake; Limon, Janusz

    2008-01-01

    Sixty-four Polish families with a history of breast and/or ovarian cancer were screened for mutations in the BRCA1/2 genes using a combination of denaturing high performance liquid chromatography (DHPLC) and sequencing. Two thirds (43/64; 67%) of the families were found to carry deleterious mutations, of which the most frequent were BRCA1 5382insC (n=22/43; 51%) and Cys61Gly (n=9/43; 20%). Two other recurrent mutations were BRCA1 185delAG (n=3) and 3819del5 (n=4), together accounting for 16% of the 43 mutation-positive cases. We also found three novel mutations (BRCA1 2991del5, BRCA2 6238ins2del21 and 8876delC) which combined with findings from our earlier study of 60 Northern Polish families. Moreover, screening of 43 BRCA1/2 negative families for the presence of large rearrangements by multiplex ligation-dependent probe amplification (MLPA) resulted in the finding of two additional BRCA1 mutations: a deletion of exons 1A, 1B and 2, and a deletion of exons 17-19, both present in single families. We conclude that the Polish population has a diverse mutation spectrum influenced by strong founder effects. However, families with strong breast/ovarian cancer history who are negative for these common mutations should be offered a complete BRCA gene screening, including MLPA analysis.

  1. Efficacy versus effectiveness of clinical genetic testing criteria for BRCA1 and BRCA2 hereditary mutations in incident breast cancer.

    PubMed

    Nilsson, Martin P; Winter, Christof; Kristoffersson, Ulf; Rehn, Martin; Larsson, Christer; Saal, Lao H; Loman, Niklas

    2017-01-24

    Increasing evidence supports the benefit of identifying BRCA1 and BRCA2 germline mutations in early breast cancer. Selection of patients for genetic testing is based on defined criteria taking individual and family history related factors into account. It is important to make a distinction between efficacy and effectiveness of BRCA testing criteria. Efficacy can be defined as the performance under ideal circumstances, whereas effectiveness refers to its real life performance. To allow for an unbiased and detailed evaluation of efficacy and effectiveness of the Swedish BRCA testing criteria, we retrospectively analyzed a prospectively collected cohort of 273 breast cancer patients from the well-characterized, population-based, single-site All Breast Cancer in Malmö (ABiM) study. The patients were diagnosed with breast cancer during the years 2007 through 2009. Out of 20 mutation carriers identified, 13 fulfilled Swedish criteria at time of diagnosis. Thus, the efficacy of these criteria was 65%. Excluding three patients in whom a mutation was already known at time of diagnosis, only 3/17 had been identified in the clinical routine, corresponding to an effectiveness of 18%. Here we detail the reasons why mutation carriers in our cohort were not detected though routine health care. In conclusion, effectiveness of BRCA testing criteria was much lower than efficacy. Our results indicate that current testing criteria and procedures associated with BRCA1 and BRCA2 testing are insufficient. There is room for improvement of their efficacy, but even more so regarding effectiveness. Clinical BRCA testing routines need to be critically revised.

  2. The rate of recurrent BRCA1, BRCA2, and TP53 mutations in the general population, and unselected ovarian cancer cases, in Belo Horizonte, Brazil.

    PubMed

    Schayek, Hagit; De Marco, Luiz; Starinsky-Elbaz, Sigal; Rossette, Mariana; Laitman, Yael; Bastos-Rodrigues, Luciana; da Silva Filho, Agnaldo Lopes; Friedman, Eitan

    2016-01-01

    In Brazil, several recurring mutations in BRCA1 and BRCA2 and a TP53 mutation (R337H) have been reported in high risk breast cancer cases. We hypothesized that these recurring mutations may also be detected in the general population and ovarian cancer cases in the state of Minas Gerais. To test this notion, participants were recruited from the outpatient and the Gynecological clinic in the UFMG Medical Center in Belo Horizonte, Minas Gerais, Brazil. BRCA1 (c.68_69delAG, c.5266dupC, c.181T>G, c.4034delA, c.5123C>A), BRCA2 (c.5946delT, c.8537_8538delAG, 4936_4939delGAAA), the c.156_157insAlu* BRCA2 and the c.1010G>A *TP53 mutation were genotyped using validated techniques. Overall, 513 cancer free participants (273 men) (mean age 47.7 ± 15.1 years) and 103 ovarian cancer cases (mean age at diagnosis 58.7 ± 9.6 years) were studied. None of the participants were found to carry any of the genotyped mutations. We conclude that the recurring mutations in BRCA1, BRCA2 and TP53 cannot be detected in the general population or consecutive ovarian cancer cases in this geographical region in Brazil.

  3. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

    PubMed

    Vigorito, Elena; Kuchenbaecker, Karoline B; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A; Andrulis, Irene L; Arun, Banu K; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Chan, Salina B; Claes, Kathleen B M; Cohn, David E; Cook, Jackie; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; Pauw, Antoine de; Delnatte, Capucine; Diez, Orland; Domchek, Susan M; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K; Goldgar, David E; Hake, Christopher R; Hansen, Thomas V O; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B L; Houdayer, Claude; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Vijai, Joseph; Karlan, Beth Y; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R; Montagna, Marco; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-Ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C; Rookus, Matti A; Ross, Eric A; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F; Slavin, Thomas P; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J; Greene, Mark H; Couch, Fergus J; Offit, Kenneth; Pharoah, Paul D P; Chenevix-Trench, Georgia; Antoniou, Antonis C

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

  4. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Vigorito, Elena; Kuchenbaecker, Karoline B.; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A.; Andrulis, Irene L.; Arun, Banu K.; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Chan, Salina B.; Claes, Kathleen B. M.; Cohn, David E.; Cook, Jackie; Daly, Mary B.; Damiola, Francesca; Davidson, Rosemarie; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Domchek, Susan M.; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F.; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D. Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D.; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A.; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K.; Goldgar, David E.; Hake, Christopher R.; Hansen, Thomas V. O.; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B. L.; Houdayer, Claude; Hulick, Peter J.; Imyanitov, Evgeny N.; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M.; Vijai, Joseph; Karlan, Beth Y.; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L.; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R.; Montagna, Marco; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I.; Ong, Kai-ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M.; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C.; Rookus, Matti A.; Ross, Eric A.; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F.; Slavin, Thomas P.; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I.; Tea, Muy-Kheng; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J.; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N.; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J.; Greene, Mark H.; Couch, Fergus J.; Offit, Kenneth; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. PMID:27463617

  5. Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT Study

    PubMed Central

    Bancroft, Elizabeth K.; Page, Elizabeth C.; Castro, Elena; Lilja, Hans; Vickers, Andrew; Sjoberg, Daniel; Assel, Melissa; Foster, Christopher S.; Mitchell, Gillian; Drew, Kate; Mæhle, Lovise; Axcrona, Karol; Evans, D. Gareth; Bulman, Barbara; Eccles, Diana; McBride, Donna; van Asperen, Christi; Vasen, Hans; Kiemeney, Lambertus A.; Ringelberg, Janneke; Cybulski, Cezary; Wokolorczyk, Dominika; Selkirk, Christina; Hulick, Peter J.; Bojesen, Anders; Skytte, Anne-Bine; Lam, Jimmy; Taylor, Louise; Oldenburg, Rogier; Cremers, Ruben; Verhaegh, Gerald; van Zelst-Stams, Wendy A.; Oosterwijk, Jan C.; Blanco, Ignacio; Salinas, Monica; Cook, Jackie; Rosario, Derek J.; Buys, Saundra; Conner, Tom; Ausems, Margreet G.; Ong, Kai-ren; Hoffman, Jonathan; Domchek, Susan; Powers, Jacquelyn; Teixeira, Manuel R.; Maia, Sofia; Foulkes, William D.; Taherian, Nassim; Ruijs, Marielle; den Enden, Apollonia T. Helderman-van; Izatt, Louise; Davidson, Rosemarie; Adank, Muriel A.; Walker, Lisa; Schmutzler, Rita; Tucker, Kathy; Kirk, Judy; Hodgson, Shirley; Harris, Marion; Douglas, Fiona; Lindeman, Geoffrey J.; Zgajnar, Janez; Tischkowitz, Marc; Clowes, Virginia E.; Susman, Rachel; Ramón y Cajal, Teresa; Patcher, Nicholas; Gadea, Neus; Spigelman, Allan; van Os, Theo; Liljegren, Annelie; Side, Lucy; Brewer, Carole; Brady, Angela F.; Donaldson, Alan; Stefansdottir, Vigdis; Friedman, Eitan; Chen-Shtoyerman, Rakefet; Amor, David J.; Copakova, Lucia; Barwell, Julian; Giri, Veda N.; Murthy, Vedang; Nicolai, Nicola; Teo, Soo-Hwang; Greenhalgh, Lynn; Strom, Sara; Henderson, Alex; McGrath, John; Gallagher, David; Aaronson, Neil; Ardern-Jones, Audrey; Bangma, Chris; Dearnaley, David; Costello, Philandra; Eyfjord, Jorunn; Rothwell, Jeanette; Falconer, Alison; Gronberg, Henrik; Hamdy, Freddie C.; Johannsson, Oskar; Khoo, Vincent; Kote-Jarai, Zsofia; Lubinski, Jan; Axcrona, Ulrika; Melia, Jane; McKinley, Joanne; Mitra, Anita V.; Moynihan, Clare; Rennert, Gad; Suri, Mohnish; Wilson, Penny; Killick, Emma; Moss, Sue; Eeles, Rosalind A.

    2014-01-01

    Background Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. Objective To report the first year's screening results for all men at enrolment in the study. Design, setting and participants We recruited men aged 40–69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy. Outcome measurements and statistical analysis PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. Results and limitations We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%—double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. Conclusions The IMPACT screening network will be useful

  6. The impact of contralateral mastectomy on mortality in BRCA1 and BRCA2 mutation carriers with breast cancer.

    PubMed

    Narod, Steven A

    2011-07-01

    Among women with breast cancer and a BRCA1 or BRCA2 mutation, the lifetime risk of breast cancer may be as high as 40%. Many physicians recommend prophylactic contralateral mastectomy, which is an effective measure of minimising the risk of contralateral cancer. The benefits of preventive contralateral mastectomy are apparent within 10 years, in terms of preventing cancer, but a much longer time period is required in order to demonstrate a reduction in mortality. Under the simple model presented here, among women who retain the contralateral breast, 0.4% of women are expected to die of contralateral breast cancer within 5 years, but 6.8% are expected to die at 20 years from diagnosis. These unnecessary deaths can be prevented by bilateral mastectomy.

  7. Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic

    PubMed Central

    Winter, C.; Nilsson, M. P.; Olsson, E.; George, A. M.; Chen, Y.; Kvist, A.; Törngren, T.; Vallon-Christersson, J.; Hegardt, C.; Häkkinen, J.; Jönsson, G.; Grabau, D.; Malmberg, M.; Kristoffersson, U.; Rehn, M.; Gruvberger-Saal, S. K.; Larsson, C.; Borg, Å.; Loman, N.; Saal, L. H.

    2016-01-01

    Background A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear. Patients and methods Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden. Results Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years). Conclusions In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling. PMID:27194814

  8. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Osorio, Ana; Milne, Roger L; Kuchenbaecker, Karoline; Vaclová, Tereza; Pita, Guillermo; Alonso, Rosario; Peterlongo, Paolo; Blanco, Ignacio; de la Hoya, Miguel; Duran, Mercedes; Díez, Orland; Ramón Y Cajal, Teresa; Konstantopoulou, Irene; Martínez-Bouzas, Cristina; Andrés Conejero, Raquel; Soucy, Penny; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Swe-Brca; Arver, Brita; Rantala, Johanna; Loman, Niklas; Ehrencrona, Hans; Olopade, Olufunmilayo I; Beattie, Mary S; Domchek, Susan M; Nathanson, Katherine; Rebbeck, Timothy R; Arun, Banu K; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; John, Esther M; Whittemore, Alice S; Daly, Mary B; Southey, Melissa; Hopper, John; Terry, Mary B; Buys, Saundra S; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Steele, Linda; Neuhausen, Susan L; Ding, Yuan Chun; Hansen, Thomas V O; Jønson, Lars; Ejlertsen, Bent; Gerdes, Anne-Marie; Infante, Mar; Herráez, Belén; Moreno, Leticia Thais; Weitzel, Jeffrey N; Herzog, Josef; Weeman, Kisa; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Bonanni, Bernardo; Mariette, Frederique; Volorio, Sara; Viel, Alessandra; Varesco, Liliana; Papi, Laura; Ottini, Laura; Tibiletti, Maria Grazia; Radice, Paolo; Yannoukakos, Drakoulis; Garber, Judy; Ellis, Steve; Frost, Debra; Platte, Radka; Fineberg, Elena; Evans, Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Eccles, Diana; Cook, Jackie; Hodgson, Shirley; Brewer, Carole; Tischkowitz, Marc; Douglas, Fiona; Porteous, Mary; Side, Lucy; Walker, Lisa; Morrison, Patrick; Donaldson, Alan; Kennedy, John; Foo, Claire; Godwin, Andrew K; Schmutzler, Rita Katharina; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hans Jörg; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M; Mazoyer, Sylvie; Damiola, Francesca; Poppe, Bruce; Claes, Kathleen; Piedmonte, Marion; Tucker, Kathy; Backes, Floor; Rodríguez, Gustavo; Brewster, Wendy; Wakeley, Katie; Rutherford, Thomas; Caldés, Trinidad; Nevanlinna, Heli; Aittomäki, Kristiina; Rookus, Matti A; van Os, Theo A M; van der Kolk, Lizet; de Lange, J L; Meijers-Heijboer, Hanne E J; van der Hout, A H; van Asperen, Christi J; Gómez Garcia, Encarna B; Hoogerbrugge, Nicoline; Collée, J Margriet; van Deurzen, Carolien H M; van der Luijt, Rob B; Devilee, Peter; Hebon; Olah, Edith; Lázaro, Conxi; Teulé, Alex; Menéndez, Mireia; Jakubowska, Anna; Cybulski, Cezary; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Johannsson, Oskar Th; Maugard, Christine; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R; Healey, Sue; Investigators, Kconfab; Olswold, Curtis; Guidugli, Lucia; Lindor, Noralane; Slager, Susan; Szabo, Csilla I; Vijai, Joseph; Robson, Mark; Kauff, Noah; Zhang, Liying; Rau-Murthy, Rohini; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Geschwantler Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Berger, Andreas; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Lejbkowicz, Flavio; Andrulis, Irene; Mulligan, Anna Marie; Glendon, Gord; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Thomassen, Mads; Kruse, Torben A; Jensen, Uffe Birk; Friedman, Eitan; Laitman, Yael; Shimon, Shani Paluch; Simard, Jacques; Easton, Douglas F; Offit, Kenneth; Couch, Fergus J; Chenevix-Trench, Georgia; Antoniou, Antonis C; Benitez, Javier

    2014-04-01

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

  9. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Osorio, Ana; Milne, Roger L.; Kuchenbaecker, Karoline; Vaclová, Tereza; Pita, Guillermo; Alonso, Rosario; Peterlongo, Paolo; Blanco, Ignacio; de la Hoya, Miguel; Duran, Mercedes; Díez, Orland; Ramón y Cajal, Teresa; Konstantopoulou, Irene; Martínez-Bouzas, Cristina; Andrés Conejero, Raquel; Soucy, Penny; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; SWE-BRCA; Arver, Brita; Rantala, Johanna; Loman, Niklas; Ehrencrona, Hans; Olopade, Olufunmilayo I.; Beattie, Mary S.; Domchek, Susan M.; Nathanson, Katherine; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; John, Esther M.; Whittemore, Alice S.; Daly, Mary B.; Southey, Melissa; Hopper, John; Terry, Mary B.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Steele, Linda; Neuhausen, Susan L.; Ding, Yuan Chun; Hansen, Thomas v. O.; Jønson, Lars; Ejlertsen, Bent; Gerdes, Anne-Marie; Infante, Mar; Herráez, Belén; Moreno, Leticia Thais; Weitzel, Jeffrey N.; Herzog, Josef; Weeman, Kisa; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Bonanni, Bernardo; Mariette, Frederique; Volorio, Sara; Viel, Alessandra; Varesco, Liliana; Papi, Laura; Ottini, Laura; Tibiletti, Maria Grazia; Radice, Paolo; Yannoukakos, Drakoulis; Garber, Judy; Ellis, Steve; Frost, Debra; Platte, Radka; Fineberg, Elena; Evans, Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Eccles, Diana; Cook, Jackie; Hodgson, Shirley; Brewer, Carole; Tischkowitz, Marc; Douglas, Fiona; Porteous, Mary; Side, Lucy; Walker, Lisa; Morrison, Patrick; Donaldson, Alan; Kennedy, John; Foo, Claire; Godwin, Andrew K.; Schmutzler, Rita Katharina; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hans Jörg; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Damiola, Francesca; Poppe, Bruce; Claes, Kathleen; Piedmonte, Marion; Tucker, Kathy; Backes, Floor; Rodríguez, Gustavo; Brewster, Wendy; Wakeley, Katie; Rutherford, Thomas; Caldés, Trinidad; Nevanlinna, Heli; Aittomäki, Kristiina; Rookus, Matti A.; van Os, Theo A. M.; van der Kolk, Lizet; de Lange, J. L.; Meijers-Heijboer, Hanne E. J.; van der Hout, A. H.; van Asperen, Christi J.; Gómez Garcia, Encarna B.; Hoogerbrugge, Nicoline; Collée, J. Margriet; van Deurzen, Carolien H. M.; van der Luijt, Rob B.; Devilee, Peter; HEBON; Olah, Edith; Lázaro, Conxi; Teulé, Alex; Menéndez, Mireia; Jakubowska, Anna; Cybulski, Cezary; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Johannsson, Oskar Th.; Maugard, Christine; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R.; Healey, Sue; Investigators, kConFab; Olswold, Curtis; Guidugli, Lucia; Lindor, Noralane; Slager, Susan; Szabo, Csilla I.; Vijai, Joseph; Robson, Mark; Kauff, Noah; Zhang, Liying; Rau-Murthy, Rohini; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Geschwantler Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Berger, Andreas; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Lejbkowicz, Flavio; Andrulis, Irene; Mulligan, Anna Marie; Glendon, Gord; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Friedman, Eitan; Laitman, Yael; Shimon, Shani Paluch; Simard, Jacques; Easton, Douglas F.; Offit, Kenneth; Couch, Fergus J.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Benitez, Javier

    2014-01-01

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10−3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10−3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied. PMID:24698998

  10. DHPLC/SURVEYOR nuclease: a sensitive, rapid and affordable method to analyze BRCA1 and BRCA2 mutations in breast cancer families.

    PubMed

    Pilato, Brunella; De Summa, Simona; Danza, Katia; Papadimitriou, Stavros; Zaccagna, Paolo; Paradiso, Angelo; Tommasi, Stefania

    2012-09-01

    Hereditary breast cancer accounts for about 10% of all breast cancers and BRCA1 and BRCA2 genes have been identified as validated susceptibility genes for this pathology. Testing for BRCA gene mutations is usually based on a pre-screening approach, such as the partial denaturation DHPLC method, and capillary direct sequencing. However, this approach is time consuming due to the large size of BRCA1 and BRCA2 genes. Recently, a new low cost and time saving DHPLC protocol has been developed to analyze gene mutations by using SURVEYOR(®) Nuclease digestion and DHPLC analysis. A subset of 90 patients, enrolled in the Genetic Counseling Program of the National Cancer Centre of Bari (Italy), was performed to validate this approach. Previous retrospective analysis showed that 9/90 patients (10%) were mutated in BRCA1 and BRCA2 genes and these data were confirmed by the present approach. DNA samples underwent touchdown PCR and, subsequently, SURVEYOR(®) nuclease digestion. BRCA1 and BRCA2 amplicons were divided into groups depending on amplicon size to allow multiamplicon digestion. The product of this reaction were analyzed on Transgenomic WAVE Nucleic Acid High Sensitivity Fragment Analysis System. The operator who performed the DHPLC surveyor approach did not know the sequencing results at that time. The SURVEYOR(®) Nuclease DHPLC approach was able to detect all alterations with a sensitivity of 95%. Furthermore, in order to save time and reagents, a multiamplicon setting preparation was validated.

  11. Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence.

    PubMed

    de Juan Jiménez, Inmaculada; García Casado, Zaida; Palanca Suela, Sarai; Esteban Cardeñosa, Eva; López Guerrero, José Antonio; Segura Huerta, Ángel; Chirivella González, Isabel; Sánchez Heras, Ana Beatriz; Juan Fita, Ma José; Tena García, Isabel; Guillen Ponce, Carmen; Martínez de Dueñas, Eduardo; Romero Noguera, Ignacio; Salas Trejo, Dolores; Goicoechea Sáez, Mercedes; Bolufer Gilabert, Pascual

    2013-12-01

    During the first 6 years of the Program of Genetic Counselling in Cancer of Valencia (eastern Spain), 310 mutations (155 in BRCA1 and 155 in BRCA2) in 1,763 hereditary breast (BC) and ovarian cancer (OC) families were identified. Of the mutations found 105 were distinct (53 in BRCA1 and 52 in BRCA2), eight new and 37 recurrent. Two of the novel mutations were frame-shift placed in exons 2 and 11 of BRCA1 and the remaining six were placed in BRCA2; four frame-shift (three in exon 11 and one in exon 23), one deletion of the entire exon 19 and one in the intervening sequence of exon 22. The BRCA1 mutations with higher recurrence were c.66_68delAG, c.5123C > A, c.1961delA, c.3770_3771delAG and c.5152+5G > A that covered 45.2% of mutations of this gene. The age of onset of BCs of c.68_69delAG mutation carriers occurs later than for the other recurrent mutations of this gene (45 vs. 37 years; p = 0.008). The BRCA2 mutations with higher recurrence were c.9026_9030delATCAT, c.3264insT and c.8978_8991del14 which represented 43.2% of all mutations in this gene, being the most recurrent mutation by far c.9026_9030delATCAT that represents 21.3% of BRCA2 mutations and 10.6% of all mutations. Probands with family histories of BC and OC, or OC and/or BC in at least two first degree relatives, were the more likely to have BRCA1/BRCA2 mutations (35.2% of the total mutations). And that most BRCA1mutations (73.19% mutations) occurred in probands with early-onset BC or with family history of OC.

  12. Tetraploidy in BRCA2 breast tumours.

    PubMed

    Jonsdottir, Asta Bjork; Stefansson, Olafur Andri; Bjornsson, Johannes; Jonasson, Jon G; Ogmundsdottir, Helga M; Eyfjord, Jorunn E

    2012-02-01

    Tetraploidy and aneuploidy can be caused by cell division errors and are frequently observed in many human carcinomas. We have recently reported delayed cytokinesis in primary human fibroblasts from BRCA2 mutation carriers, implying a function for the BRCA2 tumour suppressor in completion of cell division. Here, we address ploidy aberrations in breast tumours derived from BRCA2 germline mutation carriers. Ploidy aberrations were evaluated from flow cytometry histograms on selected breast tumour samples (n=236), previously screened for local BRCA mutations. The ploidy between BRCA2-mutated (n=71) and matched sporadic (n=165) cancers was compared. Differences in ploidy distribution were examined with respect to molecular tumour subtypes, previously defined by immunohistochemistry on tissue microarray sections. Tetraploidy was significantly 3 times more common in BRCA2 breast cancers than sporadic. However, no differences were found in the overall ploidy distribution between BRCA2-mutation carriers and non-carriers. In BRCA2 cancers, tetraploidy was associated with luminal characteristics. The increased frequency of tetraploidy in BRCA2 associated cancers may be linked to cell division errors, particularly cytokinesis. Additionally, tetraploidy emerges predominantly in BRCA2 breast cancers displaying luminal rather than triple-negative phenotypes.

  13. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Antoniou, Antonis C; Kartsonaki, Christiana; Sinilnikova, Olga M.; Soucy, Penny; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Barile, Monica; Pensotti, Valeria; Pasini, Barbara; Dolcetti, Riccardo; Giannini, Giuseppe; Laura Putignano, Anna; Varesco, Liliana; Radice, Paolo; Mai, Phuong L.; Greene, Mark H.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Birk Jensen, Uffe; Crüger, Dorthe G.; Caligo, Maria A.; Laitman, Yael; Milgrom, Roni; Kaufman, Bella; Paluch-Shimon, Shani; Friedman, Eitan; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Ehrencrona, Hans; Melin, Beatrice; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy; Jakubowska, Ania; Lubinski, Jan; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Gorski, Bohdan; Osorio, Ana; Ramón y Cajal, Teresa; Fostira, Florentia; Andrés, Raquel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B.; Rookus, Matti A.; Hooning, Maartje J.; Nelen, Marcel R.; van der Luijt, Rob B.; van Os, Theo A.M.; van Asperen, Christi J.; Devilee, Peter; Meijers-Heijboer, Hanne E.J.; Gómez Garcia, Encarna B.; Peock, Susan; Cook, Margaret; Frost, Debra; Platte, Radka; Leyland, Jean; Gareth Evans, D.; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Ong, Kai-ren; Cook, Jackie; Douglas, Fiona; Paterson, Joan; John Kennedy, M.; Miedzybrodzka, Zosia; Godwin, Andrew; Stoppa-Lyonnet, Dominique; Buecher, Bruno; Belotti, Muriel; Tirapo, Carole; Mazoyer, Sylvie; Barjhoux, Laure; Lasset, Christine; Leroux, Dominique; Faivre, Laurence; Bronner, Myriam; Prieur, Fabienne; Nogues, Catherine; Rouleau, Etienne; Pujol, Pascal; Coupier, Isabelle; Frénay, Marc; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F.; Tea, Muy-Kheng; Pfeiler, Georg; Catharina Dressler, Anne; Hansen, Thomas v.O.; Jønson, Lars; Ejlertsen, Bent; Bjork Barkardottir, Rosa; Kirchhoff, Tomas; Offit, Kenneth; Piedmonte, Marion; Rodriguez, Gustavo; Small, Laurie; Boggess, John; Blank, Stephanie; Basil, Jack; Azodi, Masoud; Ewart Toland, Amanda; Montagna, Marco; Tognazzo, Silvia; Agata, Simona; Imyanitov, Evgeny; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Pharoah, Paul D.P.; Sucheston, Lara; Karlan, Beth Y.; Walsh, Christine S.; Olah, Edith; Bozsik, Aniko; Teo, Soo-Hwang; Seldon, Joyce L.; Beattie, Mary S.; van Rensburg, Elizabeth J.; Sluiter, Michelle D.; Diez, Orland; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Varon-Mateeva, Raymonda; Kast, Karin; Deissler, Helmut; Niederacher, Dieter; Arnold, Norbert; Gadzicki, Dorothea; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Dumont, Martine; Chiquette, Jocelyne; Tischkowitz, Marc; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Chun Ding, Yuan; Fredericksen, Zachary; Wang, Xianshu; Pankratz, Vernon S.; Couch, Fergus; Simard, Jacques; Easton, Douglas F.; Chenevix-Trench, Georgia

    2011-01-01

    Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r2 = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11–1.23, P-trend = 4.5 × 10−9 for rs2046210; HR = 1.28, 95% CI: 1.18–1.40, P-trend = 1.3 × 10−8 for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01–1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02–1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92–1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women. PMID:21593217

  14. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.

    PubMed

    Antoniou, Antonis C; Kartsonaki, Christiana; Sinilnikova, Olga M; Soucy, Penny; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Barile, Monica; Pensotti, Valeria; Pasini, Barbara; Dolcetti, Riccardo; Giannini, Giuseppe; Putignano, Anna Laura; Varesco, Liliana; Radice, Paolo; Mai, Phuong L; Greene, Mark H; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A; Birk Jensen, Uffe; Crüger, Dorthe G; Caligo, Maria A; Laitman, Yael; Milgrom, Roni; Kaufman, Bella; Paluch-Shimon, Shani; Friedman, Eitan; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Ehrencrona, Hans; Melin, Beatrice; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy; Jakubowska, Ania; Lubinski, Jan; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Gorski, Bohdan; Osorio, Ana; Ramón y Cajal, Teresa; Fostira, Florentia; Andrés, Raquel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B; Rookus, Matti A; Hooning, Maartje J; Nelen, Marcel R; van der Luijt, Rob B; van Os, Theo A M; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, Hanne E J; Gómez Garcia, Encarna B; Peock, Susan; Cook, Margaret; Frost, Debra; Platte, Radka; Leyland, Jean; Evans, D Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Ong, Kai-ren; Cook, Jackie; Douglas, Fiona; Paterson, Joan; Kennedy, M John; Miedzybrodzka, Zosia; Godwin, Andrew; Stoppa-Lyonnet, Dominique; Buecher, Bruno; Belotti, Muriel; Tirapo, Carole; Mazoyer, Sylvie; Barjhoux, Laure; Lasset, Christine; Leroux, Dominique; Faivre, Laurence; Bronner, Myriam; Prieur, Fabienne; Nogues, Catherine; Rouleau, Etienne; Pujol, Pascal; Coupier, Isabelle; Frénay, Marc; Hopper, John L; Daly, Mary B; Terry, Mary B; John, Esther M; Buys, Saundra S; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Dressler, Anne Catharina; Hansen, Thomas v O; Jønson, Lars; Ejlertsen, Bent; Barkardottir, Rosa Bjork; Kirchhoff, Tomas; Offit, Kenneth; Piedmonte, Marion; Rodriguez, Gustavo; Small, Laurie; Boggess, John; Blank, Stephanie; Basil, Jack; Azodi, Masoud; Toland, Amanda Ewart; Montagna, Marco; Tognazzo, Silvia; Agata, Simona; Imyanitov, Evgeny; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Pharoah, Paul D P; Sucheston, Lara; Karlan, Beth Y; Walsh, Christine S; Olah, Edith; Bozsik, Aniko; Teo, Soo-Hwang; Seldon, Joyce L; Beattie, Mary S; van Rensburg, Elizabeth J; Sluiter, Michelle D; Diez, Orland; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Varon-Mateeva, Raymonda; Kast, Karin; Deissler, Helmut; Niederacher, Dieter; Arnold, Norbert; Gadzicki, Dorothea; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Dumont, Martine; Chiquette, Jocelyne; Tischkowitz, Marc; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B; Neuhausen, Susan L; Chun Ding, Yuan; Fredericksen, Zachary; Wang, Xianshu; Pankratz, Vernon S; Couch, Fergus; Simard, Jacques; Easton, Douglas F; Chenevix-Trench, Georgia

    2011-08-15

    Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

  15. Does the age of breast cancer diagnosis in first-degree relatives impact on the risk of breast cancer in BRCA1 and BRCA2 mutation carriers?

    PubMed

    Semple, John; Metcalfe, Kelly A; Lubinski, Jan; Huzarski, Tomasz; Gronwald, Jacek; Armel, Susan; Lynch, Henry T; Karlan, Beth; Foulkes, William; Singer, Christian F; Neuhausen, Susan L; Eng, Charis; Iqbal, Javaid; Narod, Steven A

    2015-11-01

    The purpose of this study is to estimate the age-specific annual risks of breast cancer in a woman with a germline BRCA mutation and an affected first-degree relative according to the age of breast cancer diagnosis in the relative. Women with BRCA mutations with no previous diagnosis of breast cancer and with one first-degree relative with breast cancer were followed for breast cancers for a mean of 5.9 years (minimum 2 years). Age-specific annual breast cancer risks were calculated, according to the age of breast cancer diagnosis in the proband and the first-degree relative. 1114 cancer-free women with a BRCA mutation with a single first-degree relative with breast cancer were eligible for the study. 122 women (11.0 %) were diagnosed with incident breast cancer. The annual risk of breast cancer was 2.0 % for women with BRCA1 mutations and was 1.6 % for women with BRCA2 mutations. The age of breast cancer diagnosis in the first-degree relative did not affect the annual breast cancer risks for BRCA1 mutation carriers. For BRCA2 mutation carriers, the annual breast cancer risk was 4.5 % for women with a first-degree relative diagnosed with breast cancer under the age of 30 years and was 0.7 % for women with a relative diagnosed over the age of 60. Among women with BRCA2 mutations, a family history of early-onset breast cancer is a risk factor for developing breast cancer. Risk assessment for healthy BRCA2 mutation carriers should consider the ages of breast cancers diagnosed in first-degree relatives.

  16. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction.

    PubMed

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M; Healey, Sue; Neuhausen, Susan L; Ding, Yuan Chun; Rebbeck, Timothy R; Weitzel, Jeffrey N; Lynch, Henry T; Isaacs, Claudine; Ganz, Patricia A; Tomlinson, Gail; Olopade, Olufunmilayo I; Couch, Fergus J; Wang, Xianshu; Lindor, Noralane M; Pankratz, Vernon S; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall'Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L; Greene, Mark H; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Birk Jensen, Uffe; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernström, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Durán, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, E J; Blok, Marinus J; Aalfs, Cora M; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J; Porteous, Mary E; Walker, Lisa; Kennedy, M John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valérie; Lasset, Christine; Dreyfus, Hélène; Leroux, Dominique; Hardouin, Agnès; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frénay, Marc; Vénat-Bouvet, Laurence; Hopper, John L; Daly, Mary B; Terry, Mary B; John, Esther M; Buys, Saundra S; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V O; Jønson, Lars; Agnarsson, Bjarni A; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C; Wakeley, Katie; Boggess, John F; Basil, Jack; Schwartz, Peter E; Blank, Stephanie V; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J; Sucheston, Lara; Karlan, Beth Y; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomäki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F

    2010-12-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

  17. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

    PubMed Central

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall’Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernström, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Durán, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, E.J.; Blok, Marinus J; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valérie; Lasset, Christine; Dreyfus, Hélène; Leroux, Dominique; Hardouin, Agnès; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frénay, Marc; Vénat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alex; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jønson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomäki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

    2010-01-01

    The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers. PMID:21118973

  18. Germline mutations of DICER1 in Chinese women with BRCA1/BRCA2-negative familial breast cancer.

    PubMed

    Cao, W-M; Gao, Y; Yang, H-J; Xie, S-N; Meng, X-L; Pan, Z-W; Chen, Z-H; Huang, J; Ye, W-W; Shao, X-Y; Wang, X-J

    2014-12-18

    Germline mutations in identified breast cancer susceptibility genes account for less than 20% of Chinese familial breast cancers. Dicer is an essential component of the microRNA-producing machinery; germline mutations of DICER1 have been confirmed in familial pleuropulmonary blastoma, ovarian sex cord-stromal tumors, and other cancers. Low expression of DICER1 is frequently detected in breast cancer. However, whether germline mutations of DICER1 occur in familial breast cancers remain unknown. Sixty-five breast cancer probands from BRCA1/BRCA2-negative Chinese breast cancer families were screened for germline mutations in DICER1. In addition, 100 unrelated healthy females were enrolled as controls. A polymerase chain reaction sequencing assay was used to screen for mutations in coding regions and at the exon-intron boundaries of DICER1. All variants in introns were evaluated using the NNSplice software to determine the potential splicing effect. A total of 12 germline variants were found, including 11 variants in introns and 1 variant in the 3'-non-coding region. Four variants (IVS8-205 C>T, IVS11+131 delGAAA, IVS16+42 delTA, and IVS19+160 T>C) were novel. Three variants (IVS11+105 C>T, IVS16+42 delTA, and 6095 T>A) may affect splice sites. None of the observed variants appeared to be disease-related, suggesting that germline mutations in DICER1 are rare or absent in familial breast cancer patients.

  19. The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation.

    PubMed

    Valentini, Adriana; Lubinski, Jan; Byrski, Tomasz; Ghadirian, Parviz; Moller, Pal; Lynch, Henry T; Ainsworth, Peter; Neuhausen, Susan L; Weitzel, Jeffrey; Singer, Christian F; Olopade, Olufunmilayo I; Saal, Howard; Lyonnet, Dominique Stoppa; Foulkes, William D; Kim-Sing, Charmaine; Manoukian, Siranoush; Zakalik, Dana; Armel, Susan; Senter, Leigha; Eng, Charis; Grunfeld, Eva; Chiarelli, Anna M; Poll, Aletta; Sun, Ping; Narod, Steven A

    2013-11-01

    Physicians are often approached by young women with a BRCA mutation and a recent history of breast cancer who wish to have a baby. They wish to know if pregnancy impacts upon their future risks of cancer recurrence and survival. To date, there is little information on the survival experience of women who carry a mutation in one of the BRCA genes and who become pregnant. From an international multi-center cohort study of 12,084 women with a BRCA1 or BRCA2 mutation, we identified 128 case subjects who were diagnosed with breast cancer while pregnant or who became pregnant after a diagnosis of breast cancer. These women were age-matched to 269 mutation carriers with breast cancer who did not become pregnant (controls). Subjects were followed from the date of breast cancer diagnosis until the date of last follow-up or death from breast cancer. The Kaplan-Meier method was used to estimate 15-year survival rates. The hazard ratio for survival associated with pregnancy was calculated using a left-truncated Cox proportional hazard model, adjusting for other prognostic factors. Among women who were diagnosed with breast cancer when pregnant or who became pregnant thereafter, the 15-year survival rate was 91.5 %, compared to a survival of 88.6 % for women who did not become pregnant (adjusted hazard ratio = 0.76; 95 % CI 0.31-1.91; p = 0.56). Pregnancy concurrent with or after a diagnosis of breast cancer does not appear to adversely affect survival among BRCA1/2 mutation carriers.

  20. Second primary breast cancer in BRCA1 and BRCA2 mutation carriers: 10-year cumulative incidence in the Breast Cancer Family Registry.

    PubMed

    Menes, Tehillah S; Terry, Mary Beth; Goldgar, David; Andrulis, Irene L; Knight, Julia A; John, Esther M; Liao, Yuyan; Southey, Melissa; Miron, Alexander; Chung, Wendy; Buys, Saundra S

    2015-06-01

    BReast CAncer genes 1 and 2 (BRCA1 and BRCA2) mutation carriers diagnosed with breast cancer are at increased risk of developing a second primary breast cancer. Data from high-risk clinics may be subject to different biases which can cause both over and underestimation of this risk. Using data from a large multi-institutional family registry we estimated the 10-year cumulative risk of second primary breast cancer including more complete testing information on family members. We prospectively followed 800 women diagnosed with breast cancer from the Breast Cancer Family Registry (BCFR) who were carriers of a BRCA1 or BRCA2 pathogenic mutation or a variant of unknown clinical significance. In order to limit survival and ascertainment bias, cases were limited to those diagnosed with a first primary breast cancer from 1994 to 2001 and enrolled in the BCFR within 3 years after their cancer diagnosis. We excluded women enrolled after being diagnosed with a second breast cancer. We calculated 10-year incidence of second primary breast cancers. The 10-year incidence of a second primary breast cancer was highest in BRCA1 mutation carriers (17 %; 95 % CI 11-25 %), with even higher estimates in those first diagnosed under the age of 40 (21 %; 95 % CI 13-34 %). Lower rates were found in BRCA2 mutation carriers (7 %; 95 % CI 3-15 %) and women with a variant of unknown clinical significance (6 %; 95 % CI 4-9 %). Whereas the cumulative 10-year incidence of second primary breast cancer is high in BRCA1 mutation carriers, the estimates in BRCA2 mutation carriers and women with variants of unknown clinical significance are similar to those reported in women with sporadic breast cancer.

  1. Performance of multiplicom's BRCA MASTR Dx kit on the detection of BRCA1 and BRCA2 mutations in fresh frozen ovarian and breast tumor samples

    PubMed Central

    Badoer, Cindy; Garrec, Céline; Goossens, Dirk; Ellison, Gillian; Mills, John; Dzial, Mélina; Housni, Hakim El; Berwouts, Sarah; Concolino, Paola; Guevellou, Virginie Guibert-Le; Delnatte, Capucine; Favero, Jurgen Del

    2016-01-01

    Next-generation sequencing (NGS) has enabled new approaches for detection of mutations in the BRCA1 and BRCA2 genes responsible for hereditary breast and ovarian cancer (HBOC). The search for germline mutations in the BRCA1 and BRCA2 genes is of importance with respect to oncogenetic and surgical (bilateral mastectomy, ovariectomy) counselling. Testing tumor material for BRCA mutations is of increasing importance for therapeutic decision making as the poly ADP ribose polymerase (PARP) inhibitor, olaparib, is now available to treat patients with specific forms of ovarian cancer and BRCA mutations. Molecular genetics laboratories should develop reliable and sensitive techniques for the complete analysis of the BRCA1 and BRCA2 genes. This is a challenge due to the size of the coding sequence of the BRCA1/2 genes, the absence of hot spot mutations, and particularly by the lower DNA quality obtained from Formalin-Fixed Paraffin-Embedded (FFPE) tissue. As a result, a number of analyses are uninterpretable and do not always provide a result to the clinician, limiting the optimal therapeutic management of patients. The availability of Fresh Frozen Tissue (FFT) for some laboratories and the excellent quality of the DNA extracted from it offers an alternative. For this reason, we evaluated Multiplicom's BRCA MASTR Dx assay on a set of 97 FFT derived DNA samples, in combination with the MID for Illumina MiSeq for BRCA1 and BRCA2 mutation detection. We obtained interpretable NGS results for all tested samples and showed > 99,7% sensitivity, specificity and accuracy. PMID:27793035

  2. Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.

    PubMed

    Carraro, Dirce Maria; Koike Folgueira, Maria Aparecida Azevedo; Garcia Lisboa, Bianca Cristina; Ribeiro Olivieri, Eloisa Helena; Vitorino Krepischi, Ana Cristina; de Carvalho, Alex Fiorini; de Carvalho Mota, Louise Danielle; Puga, Renato David; do Socorro Maciel, Maria; Michelli, Rodrigo Augusto Depieri; de Lyra, Eduardo Carneiro; Grosso, Stana Helena Giorgi; Soares, Fernando Augusto; Achatz, Maria Isabel Alves de Souza Waddington; Brentani, Helena; Moreira-Filho, Carlos Alberto; Brentani, Maria Mitzi

    2013-01-01

    Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.

  3. Phenocopy breast cancer rates in Israeli BRCA1 BRCA2 mutation carrier families: is the risk increased in non-carriers?

    PubMed

    Bernholtz, Shiri; Laitman, Yael; Kaufman, Bella; Shimon-Paluch, Shnai; Friedman, Eitan

    2012-04-01

    BRCA1 and BRCA2 mutation carriers have an increased risk for developing breast (and ovarian) cancer. Non-carriers from within such families (=true negatives) are counseled that their risk for developing breast cancer is similar to that of the average-risk population. Breast cancer diagnosed in a non-carrier from a family with a known mutation is coined phenocopy. The rate of breast cancer phenocopy and the risk for breast cancer in true negatives are unsettled. The rate of phenocopy breast cancer was assessed in non-carriers from Jewish families with a BRCA1 or BRCA2 mutation, identified at the Sheba medical center. Analysis was performed by t test for comparison of mean age at counseling or breast cancer diagnosis, and by calculating a standardized incidence ratio (SIR). Overall, 1318 females from 884 mutation carrying families (620 with BRCA1 264 with BRCA2 mutations) were genotyped, of whom 307 women from 245 families were assigned a true negative status (mean age at counseling 43.01 ± 13.03 years (range 19.7-92.8 years). Of these true negatives, 20 women (6.51-2.26% of families) developed breast cancer at a mean age of 54.1 ± 12.9 years (range 48.1 -60.1 years). The SIR for breast cancer in true negatives was not significantly different than the expected in the average-risk Israeli population [observed 20-expected 23.8 cases SIR = 0.84, 95% CI (0.51, 1.30)]. The rate of phenocopy breast cancer in non-carriers from Israeli BRCA1 BRCA2 mutation carrier families is 2.26% with no increased breast cancer risk over the average-risk population.

  4. Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Wang, Xianshu; Pankratz, V Shane; Fredericksen, Zachary; Tarrell, Robert; Karaus, Mary; McGuffog, Lesley; Pharaoh, Paul D P; Ponder, Bruce A J; Dunning, Alison M; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Sinilnikova, Olga M; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Houdayer, Claude; Hogervorst, Frans B L; Hooning, Maartje J; Ligtenberg, Marjolijn J; Spurdle, Amanda; Chenevix-Trench, Georgia; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Singer, Christian F; Gschwantler-Kaulich, Daphne; Dressler, Catherina; Fink, Anneliese; Szabo, Csilla I; Zikan, Michal; Foretova, Lenka; Claes, Kathleen; Thomas, Gilles; Hoover, Robert N; Hunter, David J; Chanock, Stephen J; Easton, Douglas F; Antoniou, Antonis C; Couch, Fergus J

    2010-07-15

    Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.

  5. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer

    PubMed Central

    Machackova, Eva; Foretova, Lenka; Lukesova, Mirka; Vasickova, Petra; Navratilova, Marie; Coene, Ilse; Pavlu, Hana; Kosinova, Veronika; Kuklova, Jitka; Claes, Kathleen

    2008-01-01

    Background The incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. BRCA1 and BRCA2 mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a BRCA1 or BRCA2 gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic) during 1999–2006. Methods The complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in BRCA1 was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing. Results In 294 unrelated families (29.1% of the 1,010 probands) pathogenic mutations were identified, with 44 different BRCA1 mutations and 41 different BRCA2 mutations being detected in 204 and 90 unrelated families, respectively. In total, three BRCA1 founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly) and two BRCA2 founder mutations (c.7913_7917del5; c.8537_8538del2) represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in BRCA1 (c.302-3C>G; c.4185G>A and c.4675+1G>A) and six splice-site variants in BRCA2 (c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G) were demonstrated to result in aberrant transcripts and are considered as deleterious mutations. Conclusion This study represents an evaluation of deleterious genetic variants in the BRCA1 and 2 genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer. PMID:18489799

  6. Surgically treated ovarian endometriosis association with BRCA1 and BRCA2 mutations.

    PubMed

    Aviel-Ronen, Sarit; Soriano, David; Shmuel, Elyasaf; Schonman, Ron; Rosenblatt, Kinneret; Zadok, Oranit; Vituri, Aya; Seidman, Daniel; Barshack, Iris; Cohen, Yoram

    2014-04-01

    Endometriosis is associated with an increased risk of ovarian cancer. Few studies have also shown increased risk of breast cancer. BRCA1/2 mutations are linked to an increased risk of breast and ovarian cancers but their relation to endometriosis is unknown. The objective of this study was to examine the mutation rate of BRCA1/2 among women with surgically treated ovarian endometriosis. We collected 126 specimens from Jewish Ashkenazi women with endometriotic (76) and control non-endometriotic (50) ovarian cysts, reviewed the pathological diagnoses and extracted DNA from all samples. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), samples were examined for the founder germline mutations of BRCA1/2, most common among Ashkenazi Jews. The rate of mutations in each group was calculated and compared. BRCA1/2 mutation rate was 1/76 (1.3%) in the endometriotic cyst study group and 1/50 (2%) in the control non-endometriotic cysts, showing no statistically significant difference between the groups (p=0.84). BRCA1/2 mutation rate was similar to the previously reported rate among Jewish Ashkenazi women. BRCA1/2 mutation rates in patients with endometriotic ovarian cysts and with non-endometriotic ovarian cysts are similar. A larger cohort is required to completely exclude the possibility of an association between BRCA1/2 mutations and surgically treated endometriosis.

  7. Common genetic variation at BARD1 is not associated with Breast cancer risk in BRCA1 or BRCA2 mutation carriers

    PubMed Central

    Spurdle, Amanda B.; Marquart, Louise; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga; Wan, Fei; Chen, Xiaoqing; Beesley, Jonathan; Singer, Christian F; Dressler, Anne-Catharine; Gschwantler-Kaulich, Daphne; Blum, Joanne L.; Tung, Nadine; Weitzel, Jeff; Lynch, Henry; Garber, Judy; Easton, Douglas F.; Peock, Susan; Cook, Margaret; Oliver, Clare T.; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Davidson, Rosemarie; Chu, Carol; Eccles, Diana; Selkirk, Christina G.; Daly, Mary; Isaacs, Claudine; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Buecher, Bruno; Belotti, Muriel; Mazoyer, Sylvie; Barjhoux, Laure; Verny-Pierre, Carole; Lasset, Christine; Dreyfus, Hélène; Pujol, Pascal; Collonge-Rame, Marie-Agnès; Rookus, Matti A.; Verhoef, Senno; Kriege, Mieke; Hoogerbrugge, Nicoline; Ausems, Margreet G.E.M.; van Os, Theo A.; Wijnen, Juul; Devilee, Peter; Meijers-Heijboer, Hanne E.J.; Blok, Marinus J.; Heikkinen, Tuomas; Nevanlinna, Heli; Jakubowska, Anna; Lubiński, Jan; Huzarski, Tomasz; Byrski, Tomasz; Durocher, Francine; Couch, Fergus J.; Lindor, Noralane M.; Wang, Xianshu; Thomassen, Mads; Domchek, Susan; Nathanson, Kate; Caligo, MA; Jernström, Helena; Liljegren, Annelie; Ehrencrona, Hans; Karlsson, Per; Ganz, Patricia A.; Olopade, Olufunmilayo I.; Tomlinson, Gail; Neuhausen, Susan; Antoniou, Antonis C.; Chenevix-Trench, Georgia; Rebbeck, Timothy R.

    2011-01-01

    Background Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. Methods A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second non-independent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. Results The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95%CI: 0.71-1.15) in BRCA1 carriers and 0.87 (95%CI: 0.59-1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. Conclusion Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. Impact Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk. PMID:21393566

  8. Risk Factors for Endometrial Cancer among Women with a BRCA1 or BRCA2 Mutation: A Case Control Study

    PubMed Central

    Segev, Yakir; Rosen, Barry; Lubinski, Jan; Gronwald, Jacek; Lynch, Henry T.; Moller, Pal; Kim-Sing, Charmaine; Ghadirian, Parviz; Karlan, Beth; Eng, Charis; Gilchrist, Dawna; Neuhausen, Susan L.; Eisen, Andrea; Friedman, Eitan; Euhus, David; Ping, Sun; Narod, Steven A.

    2016-01-01

    Purpose BRCA mutation carriers may use tamoxifen for breast cancer prevention or treatment. Hormone replacement therapy is often prescribed after surgical menopause and oral contraceptives are recommended for ovarian cancer prevention. The objective of this study was to assess the impact of these medications and other risk factors on endometrial cancer risk in BRCA carriers. Methods Women with a BRCA1 or BRCA2 mutation were identified from a registry of mutation carriers. Cases were 83 women who had a diagnosis of endometrial cancer. Controls were 1027 matched women who did not develop endometrial cancer and who had an intact uterus. All women completed a baseline questionnaire, which included questions about ages at menarche and menopause, oral contraceptive use, hormone replacement therapy use, hysterectomy, oophorectomy, breast cancer history and tamoxifen use. We estimated the odds ratio associated with each risk factor in a multivariate analysis. Results No differences were found between cases and controls in terms of age at menarche, BMI, smoking, or oral contraceptive use. In a multivariate analysis, for women taking estrogen-only hormone replacement therapy, the odds ratio was 0.23 (95% CI 0.03–1.78, p = 0.16), and for women taking progesterone-only hormone replacement therapy the odds ratio was 6.91 (95% CI 0.99–98.1, p = 0.05). The adjusted odds ratio for endometrial cancer associated with a history of tamoxifen use was 3.50 (95% CI 1.51 to 8.10; p = 0.003). Conclusions The observed increased risk of associated with progesterone-only therapy merits further study. PMID:25838159

  9. Management of the asymptomatic BRCA mutation carrier

    PubMed Central

    Teller, Paige; Kramer, Rita K

    2010-01-01

    Current management of an asymptomatic BRCA mutation carrier includes early initiation and intensive cancer screening in combination with risk reduction strategies. The primary objectives of these interventions are earlier detection and cancer prevention to increase quality of life and prolonged survival. Existing recommendations are often based on the consensus of experts as there are few, supportive, randomized control trials. Management strategies for unaffected patients with BRCA mutations are continually redefined and customized as more evidence-based knowledge is acquired with regard to current intervention efficacy, mutation-related histology, and new treatment modalities. This review provides an outline of current, supported management principles, and interventions in the care of the asymptomatic BRCA mutation carrier. Topics covered include surveillance modalities and risk reduction achieved through behavioral modification, chemoprevention, and prophylactic surgery. PMID:23776357

  10. Endometrium is not the primary site of origin of pelvic high-grade serous carcinoma in BRCA1 or BRCA2 mutation carriers.

    PubMed

    Reitsma, Welmoed; Mourits, Marian J E; de Bock, Geertruida H; Hollema, Harry

    2013-04-01

    Serous endometrial intraepithelial carcinoma has been proposed to be a potential precursor lesion of pelvic high-grade serous carcinoma. If true, an increased incidence of uterine papillary serous carcinomas would be expected in BRCA1 and BRCA2 mutation carriers, who are at high-risk of developing pelvic high-grade serous carcinoma. This study explored particularly the occurrence of uterine papillary serous carcinoma, as well as other endometrial cancers, following risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 germline mutation attending a tertiary multidisciplinary clinic. A consecutive series of women with a BRCA1 or BRCA2 mutation who had undergone risk-reducing salpingo-oophorectomy without hysterectomy at the University Medical Center Groningen from January 1996 until March 2012 were followed prospectively. They were crossed with the histopathology list of endometrial cancer diagnoses reported by the Dutch nationwide pathology database PALGA. To assess the risk of endometrial cancer, a standardized incidence ratio was calculated comparing the observed with the expected number of endometrial cancer cases. Overall, 201 BRCA1 and 144 BRCA2 mutation carriers at a median age of 50 years (range, 32-78) were analyzed. After a median follow-up period of 6 years, after risk-reducing salpingo-oophorectomy, two cases of endometrial cancer were diagnosed, whereas the expected number was 0.94 cases (standardized incidence ratio 2.13; 95% confidence interval 0.24-7.69; P=0.27). Both endometrial cancer cases were of the endometrioid histological subtype. We showed that the incidence of endometrial cancer following risk-reducing salpingo-oophorectomy, especially uterine papillary serous carcinoma, in women at high-risk of developing pelvic high-grade serous carcinoma is not increased. On the basis of our data, the hypothesis of serous endometrial intraepithelial carcinoma being an important precursor lesion of pelvic high-grade serous carcinoma seems

  11. Plasma osteoprotegerin and breast cancer risk in BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Odén, Lovisa; Akbari, Mohammad; Zaman, Tasnim; Singer, Christian F.; Sun, Ping; Narod, Steven A.; Salmena, Leonardo; Kotsopoulos, Joanne

    2016-01-01

    Emerging evidence suggests a role of receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) signaling in breast cancer development. Lower osteoprotegerin (OPG) levels, the endogenous decoy receptor for RANKL which competes with RANK for binding of RANKL, has been reported among BRCA mutation carriers. Whether low OPG levels contribute to the high breast cancer risk in this population is unknown. OPG concentrations were measured in plasma of 206 cancer-free BRCA mutation carriers using an enzyme-linked immunosorbent assay. Subjects were categorized as high vs. low based on the median of the entire cohort (95 ng/mL) and followed for a new diagnosis of breast cancer. Cumulative incidence by baseline plasma OPG concentration was estimated using Kaplan-Meier survival analysis. Cox proportional hazards models were used to estimate the adjusted hazard ratios for the association between plasma OPG and breast cancer risk. Over a mean follow-up period of 6.5 years (range 0.1–18.8 years), 18 incident breast cancer cases were observed. After ten years of follow-up, the cumulative incidence of breast cancer among women with low OPG was 21%, compared to 9% among women with high OPG (P-log rank = 0.046). After multivariate adjustment, women with high plasma OPG had a significantly decreased risk of developing breast cancer, compared to women with low OPG (HR = 0.25; 95%CI 0.08–0.78; P = 0.02). These data suggest that low OPG levels are associated with an increased risk of BRCA-associated breast cancer. Targeting RANK signalling may represent a plausible, non-surgical prevention option for BRCA mutation carriers. PMID:27893411

  12. Durable Clinical Benefit of Pertuzumab in a Young Patient with BRCA2 Mutation and HER2-Overexpressing Breast Cancer Involving the Brain

    PubMed Central

    Koumarianou, Anna; Kontopoulou, Christina; Kouloulias, Vassilis; Tsionou, Christina

    2016-01-01

    Patients with HER2-positive breast cancer and brain metastases have limited treatment options, and, as a result of their poor performance status and worse prognosis, they are underrepresented in clinical trials. Not surprisingly, these patients may not be fit enough to receive any active treatment and are offered supportive therapy. BRCA2 mutations are reported to be rarely associated with HER2-overexpressing advanced breast cancer and even more rarely with brain metastases at diagnosis. We report on a BRCA2-positive breast cancer patient with metastatic disease in multiple sites, including the brain, and poor performance status who exhibited an extraordinary clinical and imaging response to the novel anti-HER2 therapy pertuzumab after multiple lines of therapy including anti-HER2 targeting. To our knowledge, the clinicopathologic and therapeutic characteristics of this patient point to a unique case and an urgent need for further investigation of pertuzumab in patients with brain metastases. PMID:27195161

  13. Durable Clinical Benefit of Pertuzumab in a Young Patient with BRCA2 Mutation and HER2-Overexpressing Breast Cancer Involving the Brain.

    PubMed

    Koumarianou, Anna; Kontopoulou, Christina; Kouloulias, Vassilis; Tsionou, Christina

    2016-01-01

    Patients with HER2-positive breast cancer and brain metastases have limited treatment options, and, as a result of their poor performance status and worse prognosis, they are underrepresented in clinical trials. Not surprisingly, these patients may not be fit enough to receive any active treatment and are offered supportive therapy. BRCA2 mutations are reported to be rarely associated with HER2-overexpressing advanced breast cancer and even more rarely with brain metastases at diagnosis. We report on a BRCA2-positive breast cancer patient with metastatic disease in multiple sites, including the brain, and poor performance status who exhibited an extraordinary clinical and imaging response to the novel anti-HER2 therapy pertuzumab after multiple lines of therapy including anti-HER2 targeting. To our knowledge, the clinicopathologic and therapeutic characteristics of this patient point to a unique case and an urgent need for further investigation of pertuzumab in patients with brain metastases.

  14. Prevalence of BRCA1 and BRCA2 mutations in non-familial breast cancer patients with high risks in Korea: the Korean Hereditary Breast Cancer (KOHBRA) Study.

    PubMed

    Son, Byung Ho; Ahn, Sei Hyun; Kim, Sung-Won; Kang, Eunyoung; Park, Sue K; Lee, Min Hyuk; Noh, Woo-Chul; Kim, Lee Su; Jung, Yongsik; Kim, Ku Sang; Noh, Dong-Young; Moon, Byung-In; Suh, Young Jin; Lee, Jeong Eon; Choi, Doo Ho; Kim, Sung Yong; Jung, Sung Hoo; Yom, Cha Kyong; Lee, Hyde; Yang, Jung-Hyun

    2012-06-01

    Prevalence and phenotype of BRCA mutation can vary by race. The purpose of this study is to evaluate the prevalence of BRCA1/2 mutations in non-familial breast cancer patients with high risks in Korea. A subset of 758 patients was selected for this study from the KOHBRA nationwide multicenter prospective cohort study. Mutations in BRCA1/2 genes were tested using fluorescent-conformation sensitive gel electrophoresis, denaturing high performance liquid chromatography or direct sequencing. Mutation of BRCA1/2 genes were identified in 65 (8.6%) patients among total 758 patients [BRCA1 mutation: 25 (3.3%), BRCA2 mutation: 40 (5.3%)]. According to risk groups, mutation of BRCA1/2 genes were identified in 53 (8.5%) of 625 early onset patients (age ≤ 40), in 22 (17.7%) of 124 bilateral breast cancer patients, in 3 (50.0%) of 6 breast and ovarian cancer patients, in one (5.9%) of 17 male breast cancer patients, in 5 cases (7.6%) of 66 multiple organ cancer patients. The most common mutation was 509C>A for BRCA1 and 7708C>T for BRCA2. The prevalence of BRCA1/2 mutations by age in early onset patients was significantly different (age <35 vs age ≥35; 10.0 vs 2.9%, p = 0.0007). BRCA1/2 mutations for non-familial Korean breast cancer patients were detected at a high rate, particularly, in patients with early onset of less than 35 years of age, bilateral breast cancer, and breast and ovarian cancer. Individualized genetic counseling should be offered for non-familial breast cancer patients with these risk factors.

  15. Compensatory functions and interdependency of the DNA-binding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex.

    PubMed

    Al Abo, Muthana; Dejsuphong, Donniphat; Hirota, Kouji; Yonetani, Yasukazu; Yamazoe, Mitsuyoshi; Kurumizaka, Hitoshi; Takeda, Shunichi

    2014-02-01

    BRCA1, BRCA2, and PALB2 are key players in cellular tolerance to chemotherapeutic agents, including camptothecin, cisplatin, and PARP inhibitor. The N-terminal segment of BRCA2 interacts with PALB2, thus contributing to the formation of the BRCA1-PALB2-BRCA2 complex. To understand the role played by BRCA2 in this complex, we deleted its N-terminal segment and generated BRCA2(Δ)(N) mutant cells. Although previous studies have suggested that BRCA1-PALB2 plays a role in the recruitment of BRCA2 to DNA-damage sites, BRCA2(Δ)(N) mutant cells displayed a considerably milder phenotype than did BRCA2(-/-) null-deficient cells. We hypothesized that the DNA-binding domain (DBD) of BRCA2 might compensate for a defect in BRCA2(ΔN) that prevented stable interaction with PALB2. To test this hypothesis, we disrupted the DBD of BRCA2 in wild-type and BRCA2(Δ)(N) cells. Remarkably, although the resulting BRCA2(Δ)(DBD) cells displayed a moderate phenotype, the BRCA2(Δ)(N+ΔDBD) cells displayed a very severe phenotype, as did the BRCA2(-/-) cells, suggesting that the N-terminal segment and the DBD play a substantially overlapping role in the functionality of BRCA2. We also showed that the formation of both the BRCA1-PALB2-BRCA2 complex and the DBD is required for efficient recruitment of BRCA2 to DNA-damage sites. Our study revealed the essential role played by both the BRCA1-PALB2-BRCA2 complex and the DBD in the functionality of BRCA2, as each can compensate for the other in the recruitment of BRCA2 to DNA-damage sites. This knowledge adds to our ability to accurately predict the efficacy of antimalignant therapies for patients carrying mutations in the BRCA2 gene.

  16. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study.

    PubMed

    Kang, Eunyoung; Seong, Moon-Woo; Park, Sue K; Lee, Jong Won; Lee, Jihyoun; Kim, Lee Su; Lee, Jeong Eon; Kim, Sung Yong; Jeong, Joon; Han, Sang Ah; Kim, Sung-Won

    2015-05-01

    The Korean Hereditary Breast Cancer (KOHBRA) study was established to evaluate the prevalence and spectrum of BRCA1/2 mutations in Korean breast cancer patients at risk for hereditary breast and ovarian cancer. A total of 2953 subjects (2403 index patients and 550 family members of affected carriers) from 36 centers participated in this study between May 2007 and December 2013. All participants received genetic counseling and BRCA genetic testing. In total, 378 mutation carriers among 2403 index patients were identified. The prevalence of BRCA mutations in specific subgroups was as follows: 22.3 % (274/1228) for breast cancer patients with a family history of breast/ovarian cancers, 8.8 % (39/441) for patients with early-onset (<35 years) breast cancer without a family history, 16.3 % (34/209) for patients with bilateral breast cancer, 4.8 % (1/21) for male patients with breast cancer, and 37.5 % (3/8) for patients with both breast and ovarian cancer. From an analysis of the mutation spectrum, 63 BRCA1 and 90 BRCA2 different mutations, including 44 novel mutations, were identified. The c.7480 (p.Arg2494Ter) mutation in BRCA2 (10.1 %) was the most commonly identified in this cohort. The KOHBRA study is the largest cohort to identify BRCA mutation carriers in Asia. The results suggest that the prevalence of BRCA mutations in familial breast cancer patients is similar to that among Western cohorts. However, some single risk factors without family histories (early-onset breast cancer, male breast cancer, or multiple organ cancers) may limit the utility of BRCA gene testing in the Korean population.

  17. Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Couch, Fergus J.; Gaudet, Mia M.; Antoniou, Antonis C.; Ramus, Susan J.; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; Wang, Xianshu; Kirchhoff, Tomas; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Healey, Sue; Sinilnikova, Olga M.; Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna Marie; Thomassen, Mads; Gerdes, Anne-Marie; Jensen, Uffe Birk; Skytte, Anne-Bine; Kruse, Torben A.; Caligo, Maria A.; von Wachenfeldt, Anna; Barbany-Bustinza, Gisela; Loman, Niklas; Soller, Maria; Ehrencrona, Hans; Karlsson, Per; Nathanson, Katherine L.; Rebbeck, Timothy R.; Domchek, Susan M.; Jakubowska, Ania; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Cybulski, Cezary; Górski, Bohdan; Osorio, Ana; Durán, Mercedes; Tejada, María Isabel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B.L.; van Os, Theo A.; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E.J.; Wijnen, Juul; Blok, Marinus J.; Kets, Marleen; Hooning, Maartje J.; Oldenburg, Rogier A.; Ausems, Margreet G.E.M.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Jacobs, Chris; Eeles, Rosalind A.; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana M.; Cole, Trevor; Cook, Jackie; Paterson, Joan; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley V.; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Side, Lucy E.; Bove, Betsy; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Fassy-Colcombet, Marion; Castera, Laurent; Cornelis, François; Mazoyer, Sylvie; Léoné, Mélanie; Boutry-Kryza, Nadia; Bressac-de Paillerets, Brigitte; Caron, Olivier; Pujol, Pascal; Coupier, Isabelle; Delnatte, Capucine; Akloul, Linda; Lynch, Henry T.; Snyder, Carrie L.; Buys, Saundra S.; Daly, Mary B.; Terry, MaryBeth; Chung, Wendy K.; John, Esther M.; Miron, Alexander; Southey, Melissa C.; Hopper, John L.; Goldgar, David E.; Singer, Christian F.; Rappaport, Christine; Tea, Muy-Kheng M.; Fink-Retter, Anneliese; Hansen, Thomas V. O.; Nielsen, Finn C.; Arason, Aðalgeir; Vijai, Joseph; Shah, Sohela; Sarrel, Kara; Robson, Mark E.; Piedmonte, Marion; Phillips, Kelly; Basil, Jack; Rubinstein, Wendy S.; Boggess, John; Wakeley, Katie; Ewart-Toland, Amanda; Montagna, Marco; Agata, Simona; Imyanitov, Evgeny N.; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Feliubadalo, Lidia; Brunet, Joan; Gayther, Simon A; Pharoah, Paul PD; Odunsi, Kunle O.; Karlan, Beth Y.; Walsh, Christine S.; Olah, Edith; Teo, Soo Hwang; Ganz, Patricia A.; Beattie, Mary S.; van Rensburg, Elizabeth J.; Dorfling, Cecelia M.; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorothea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Heinritz, Wolfram; Caldes, Trinidad; de la Hoya, Miguel; Muranen, Taru A.; Nevanlinna, Heli; Tischkowitz, Marc D.; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Lindor, Noralane M.; Fredericksen, Zachary; Pankratz, V. Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Bernard, Loris; Viel, Alessandra; Giannini, Giuseppe; Varesco, Liliana; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Easton, Douglas F.; Chenevix-Trench, Georgia; Offit, Kenneth; Simard, Jacques

    2012-01-01

    Background Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers (hazard ratio (HR)=1.17; 95%CI 1.07–1.27; p=7.42×10−4) and between rs16917302 at ZNF365 (HR=0.84; 95%CI 0.73–0.97; p=0.017) but not rs311499 at 20q13.3 (HR=1.11; 95%CI 0.94–1.31; p=0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR=1.16; 95%CI 1.05–1.29; p=3.8×10−4) and BRCA2 mutation carriers (HR=1.30; 95%CI 1.10–1.52; p=1.8×10−3). Conclusions 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. PMID:22351618

  18. Traceback: A Proposed Framework to Increase Identification and Genetic Counseling of BRCA1 and BRCA2 Mutation Carriers Through Family-Based Outreach.

    PubMed

    Samimi, Goli; Bernardini, Marcus Q; Brody, Lawrence C; Caga-Anan, Charlisse F; Campbell, Ian G; Chenevix-Trench, Georgia; Couch, Fergus J; Dean, Michael; de Hullu, Joanne A; Domchek, Susan M; Drapkin, Ronny; Spencer Feigelson, Heather; Friedlander, Michael; Gaudet, Mia M; Harmsen, Marline G; Hurley, Karen; James, Paul A; Kwon, Janice S; Lacbawan, Felicitas; Lheureux, Stephanie; Mai, Phuong L; Mechanic, Leah E; Minasian, Lori M; Myers, Evan R; Robson, Mark E; Ramus, Susan J; Rezende, Lisa F; Shaw, Patricia A; Slavin, Thomas P; Swisher, Elizabeth M; Takenaka, Masataka; Bowtell, David D; Sherman, Mark E

    2017-04-11

    In May 2016, the Division of Cancer Prevention and the Division of Cancer Control and Population Sciences, National Cancer Institute, convened a workshop to discuss a conceptual framework for identifying and genetically testing previously diagnosed but unreferred patients with ovarian cancer and other unrecognized BRCA1 or BRCA2 mutation carriers to improve the detection of families at risk for breast or ovarian cancer. The concept, designated Traceback, was prompted by the recognition that although BRCA1 and BRCA2 mutations are frequent in women with ovarian cancer, many such women have not been tested, especially if their diagnosis predated changes in testing guidelines. The failure to identify mutation carriers among probands represents a lost opportunity to prevent cancer in unsuspecting relatives through risk-reduction intervention in mutation carriers and to provide appropriate reassurances to noncarriers. The Traceback program could provide an important opportunity to reach families from racial, ethnic, and socioeconomic groups who historically have not sought or been offered genetic counseling and testing and thereby contribute to a reduction in health disparities in women with germline BRCA mutations. To achieve an interdisciplinary perspective, the workshop assembled international experts in genetics, medical and gynecologic oncology, clinical psychology, epidemiology, genomics, cost-effectiveness modeling, pathology, bioethics, and patient advocacy to identify factors to consider when undertaking a Traceback program. This report highlights the workshop deliberations with the goal of stimulating research and providing a framework for pilot studies to assess the feasibility and ethical and logistical considerations related to the development of best practices for implementation of Traceback studies.

  19. Breast MRI fibroglandular volume and parenchymal enhancement in BRCA1 and BRCA2 mutation carriers before and immediately after risk-reducing salpingo-oophorectomy.

    PubMed

    DeLeo, Michael J; Domchek, Susan M; Kontos, Despina; Conant, Emily; Chen, Jinbo; Weinstein, Susan

    2015-03-01

    OBJECTIVE. The purpose of this article is to assess the difference in fibroglandular volume and background parenchymal enhancement in BRCA1 and BRCA2 mutation carriers on contrast-enhanced breast MRI (CE-MRI) performed before and immediately after risk-reducing salpingo-oophorectomy (RRSO). MATERIALS AND METHODS. We retrospectively compared fibroglandular volume and background parenchymal enhancement in 55 female BRCA1 and BRCA2 mutation carriers before and after RRSO using standard BI-RADS categories and a paired Wilcoxon and Mann-Whitney U test. A two-sample Wilcoxon test was performed to compare fibroglandular volume and background parenchymal enhancement in women with and without subsequent breast cancer diagnosis on follow-up. RESULTS. The median time to post-RRSO CE-MRI was 8 months (range, 1-40 months). There was no difference in fibroglandular volume before and after RRSO (p = 0.65). The mean background parenchymal enhancement was 2.5 (range, 1-4) before and 1.5 (range, 1-4) after RRSO (overall range, -2.5 to 1.5; p = 0.0001). Breast cancer was detected in nine women at a median time of 4.8 years (range, 1.8-13.3 years) after RRSO. For women who received a diagnosis of breast cancer after RRSO compared with those who did not, mean background parenchymal enhancement before RRSO was 3 (range, 2-4) versus 2.5 (range, 1-4; p = 0.001), and mean background parenchymal enhancement after RRSO was 2.5 (range, 1.5-4) versus 1.5 (range 2-4; p = 0.0018). There was no difference in fibroglandular volume before and after RRSO. CONCLUSION. In BRCA1 and BRCA2 mutation carriers, we observed a significant reduction in background parenchymal enhancement on the first CE-MRI after RRSO and no significant change in fibroglandular volume. Higher background parenchymal enhancement before and after RRSO was observed in women who subsequently received a diagnosis of breast cancer. This suggests that background parenchymal enhancement, rather than fibro-glandular volume, may be a

  20. New perspective on maintenance therapies for platinum- sensitive recurrent ovarian cancer in women with germline and somatic mutations in BRCA1 and BRCA2 genes

    PubMed Central

    Vergote, I; Bours, V; Blaumeiser, B; Baurain, J-F

    2016-01-01

    Ovarian cancer (OC) is the seventh most common cancer in women. Although women diagnosed with OC are usually treated frontline with platinum-based chemotherapy, most of them relapse once treatment is halted. Therefore, maintenance therapies have been developed to secure the response and delay further chemotherapy. There are two established maintenance therapies for women affected by platinum-sensitive recurrent OC: bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, and olaparib, an inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARPi). Loss-of-function mutations in genes in the homologous recombination pathway, especially BRCA1 and BRCA2, predict higher rates of platinum sensitivity, better overall survival (OS), and better response to PARPi in women with OC. Among patients with platinum-sensitive recurrent OC, a BRCA mutation is the first genetically defined predictive marker for targeted therapy, since these patients are most likely to benefit from treatment with a PARPi, such as olaparib. In patients with platinum-sensitive recurrent OC without a BRCA mutation, bevacizumab currently seems to be the best maintenance option. Women with OC are progressively more routinely screened for germline BRCA mutations, and the implication of somatic BRCA mutations is increasingly being recognized in OC. Therefore, the recommendations should be updated to reflect the importance of both types of mutations. Together, these data highlight the fact that treatment of recurrent OC can be optimized using genomic contributions to individualize therapy and to improve treatment response. PMID:28003870

  1. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    PubMed Central

    2011-01-01

    Introduction Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models

  2. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years: a national cohort study.

    PubMed

    Saadatmand, Sepideh; Vos, Janet R; Hooning, Maartje J; Oosterwijk, Jan C; Koppert, Linetta B; de Bock, Geertruida H; Ausems, Margreet G; van Asperen, Christi J; Aalfs, Cora M; Gómez Garcia, Encarna B; Meijers-Heijboer, Hanne; Hoogerbrugge, Nicoline; Piek, Marianne; Seynaeve, Caroline; Verhoef, Cornelis; Rookus, Matti; Tilanus-Linthorst, Madeleine M

    2014-12-15

    Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised ≥60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom screening ≥60 is relevant, in the Rotterdam Family Cancer Clinic and HEBON: a nationwide prospective cohort study. Furthermore, we compared tumour stage at breast cancer diagnosis between different screening strategies in BRCA1/2 mutation carriers ≥60. Tumours >2 cm, positive lymph nodes, or distant metastases at detection were defined as "unfavourable." Of 548 BRCA1/2 mutation carriers ≥60 years in 2012, 395 (72%) did not have bilateral mastectomy before the age of 60. Of these 395, 224 (57%) had a history of breast or other invasive carcinoma. In 136 BRCA1/2 mutation carriers, we compared 148 breast cancers (including interval cancers) detected ≥60, of which 84 (57%) were first breast cancers. With biennial mammography 53% (30/57) of carcinomas were detected in unfavourable stage, compared to 21% (12/56) with annual mammography (adjusted odds ratio: 4·07, 95% confidence interval [1.79-9.28], p = 0.001). With biennial screening 40% of breast cancers were interval cancers, compared to 20% with annual screening (p = 0.016). Results remained significant for BRCA1 and BRCA2 mutation carriers, and first breast cancers separately. Over 70% of 60-year old BRCA1/2 mutation carriers remain at risk for breast cancer, of which half has prior cancers. When life expectancy is good, continuation of annual breast cancer screening of BRCA1/2 mutation carriers ≥60 is worthwhile.

  3. Sanger Sequencing for BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del Mutation Screen on Pap Smear Cytology Samples.

    PubMed

    Lee, Sin Hang; Zhou, Shaoxia; Zhou, Tianjun; Hong, Guofan

    2016-02-08

    Three sets of polymerase chain reaction (PCR) primers were designed for heminested PCR amplification of the target DNA fragments in the human genome which include the site of BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del respectively, to prepare the templates for direct Sanger sequencing screen of these three founder mutations. With a robust PCR mixture, crude proteinase K digestate of the fixed cervicovaginal cells in the liquid-based Papanicolaou (Pap) cytology specimens can be used as the sample for target DNA amplification without pre-PCR DNA extraction, purification and quantitation. The post-PCR products can be used directly as the sequencing templates without further purification or quantitation. By simplifying the frontend procedures for template preparation, the cost for screening these three founder mutations can be reduced to about US $200 per test when performed in conjunction with human papillomavirus (HPV) assays now routinely ordered for cervical cancer prevention. With this projected price structure, selective patients in a high-risk population can be tested and each provided with a set of DNA sequencing electropherograms to document the absence or presence of these founder mutations in her genome to help assess inherited susceptibility to breast and ovarian cancer in this era of precision molecular personalized medicine.

  4. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    PubMed Central

    2012-01-01

    Introduction Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers. PMID:22348646

  5. Cumulative risk of second primary contralateral breast cancer in BRCA1/BRCA2 mutation carriers with a first breast cancer: A systematic review and meta-analysis.

    PubMed

    Molina-Montes, Esther; Pérez-Nevot, Beatriz; Pollán, Marina; Sánchez-Cantalejo, Emilio; Espín, Jaime; Sánchez, María-José

    2014-12-01

    BRCA1/2 mutation carriers are at a higher risk of breast cancer and of subsequent contralateral breast cancer (CBC). This study aims to evaluate the evidence of the effect of the BRCA1/2-carriership on CBC cumulative risk in female breast cancer patients. The literature was searched in Pubmed and Embase up to June 2013 for studies on CBC risk after a first primary invasive breast cancer in female BRCA1/2 mutation carriers. A qualitative synthesis was carried out and the methodological quality of the studies evaluated. Cumulative risks of CBC after 5, 10 and 15 years since the first breast cancer diagnosis were pooled by BRCA1/2 mutation status. A total number of 20 articles, out of 1324 retrieved through the search, met the inclusion criteria: 18 retrospective and 2 prospective cohort studies. Cumulative risks of up to five studies were pooled. The cumulative 5-years risk of CBC for BRCA1 and BRCA2 mutation carriers was 15% (95% CI: 9.5%-20%) and 9% (95% CI: 5%-14%), respectively. This risk increases with time since diagnosis of the first breast cancer; the 10-years risk increased up to 27% and 19%, respectively. The 5-years cumulative risk was remarkably lower in non-BRCA carriers (3%; 95% CI: 2%-5%) and remained so over subsequent years (5%; 95% CI: 3%-7%). In conclusion, risk of CBC increases with length of time after the first breast cancer diagnosis in BRCA1/2 mutation carriers. Studies addressing the impact of treatment-related factors and clinical characteristics of the first breast cancer on this risk are warranted.

  6. Association of the Variants CASP8 D302H and CASP10 V410I with Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Engel, Christoph; Versmold, Beatrix; Wappenschmidt, Barbara; Simard, Jacques; Easton, Douglas F.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Mayes, Rebecca; Evans, D. Gareth; Eeles, Rosalind; Paterson, Joan; Brewer, Carole; McGuffog, Lesley; Antoniou, Antonis C.; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Barjhoux, Laure; Frenay, Marc; Michel, Cécile; Leroux, Dominique; Dreyfus, Helene; Toulas, Christine; Gladieff, Laurence; Uhrhammer, Nancy; Bignon, Yves-Jean; Meindl, Alfons; Arnold, Norbert; Varon-Mateeva, Raymonda; Niederacher, Dieter; Preisler-Adams, Sabine; Kast, Karin; Deissler, Helmut; Sutter, Christian; Gadzicki, Dorothea; Chenevix-Trench, Georgia; Spurdle, Amanda B.; Chen, Xiaoqing; Beesley, Jonathan; Olsson, Håkan; Kristoffersson, Ulf; Ehrencrona, Hans; Liljegren, Annelie; van der Luijt, Rob B.; van Os, Theo A.; van Leeuwen, Flora E.; Domchek, Susan M.; Rebbeck, Timothy R.; Nathanson, Katherine L.; Osorio, Ana; Cajal, Teresa Ramón y; Konstantopoulou, Irene; Benítez, Javier; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Mai, Phuong L.; Greene, Mark H.; Nevanlinna, Heli; Aittomäki, Kristiina; Szabo, Csilla I.; Caldes, Trinidad; Couch, Fergus J.; Andrulis, Irene L.; Godwin, Andrew K.; Hamann, Ute; Schmutzler, Rita K.

    2011-01-01

    Background The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. Methods To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIM-BA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Results The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76–0.97; Ptrend = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53–0.89; Ptrend = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. Conclusions CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. Impact The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers. PMID:20978178

  7. The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers.

    PubMed

    Jakubowska, Anna; Rozkrut, Dominik; Antoniou, Antonis; Hamann, Ute; Lubinski, Jan

    2010-06-01

    Integrins containing the beta(3) subunit are key players in tumor growth and metastasis. A functional Leu33Pro polymorphism (rs5918) in the beta(3) subunit of the integrin gene (ITGB3) has previously been suggested to act as a modifier of ovarian cancer risk in Polish BRCA1 mutation carriers. To investigate the association further, we genotyped 9,998 BRCA1 and 5,544 BRCA2 mutation carriers from 34 studies from the Consortium of Investigators of Modifiers of BRCA1/2 for the ITGB3 Leu33Pro polymorphism. Data were analysed within a Cox-proportional hazards framework using a retrospective likelihood approach. There was marginal evidence that the ITGB3 polymorphism was associated with an increased risk of ovarian cancer for BRCA1 mutation carriers (per-allele Hazard Ratio (HR) 1.11, 95% CI 1.00-1.23, p-trend 0.05). However, when the original Polish study was excluded from the analysis, the polymorphism was no longer significantly associated with ovarian cancer risk (HR 1.07, 95% CI 0.96-1.19, p-trend 0.25). There was no evidence of an association with ovarian cancer risk for BRCA2 mutation carriers (HR 1.09, 95% CI 0.89-1.32). The polymorphism was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers. The ITGB3 Leu33Pro polymorphism does not modify breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

  8. Differences in the frequency and distribution of BRCA1 and BRCA2 mutations in breast/ovarian cancer cases from the Basque country with respect to the Spanish population: implications for genetic counselling.

    PubMed

    Beristain, E; Martínez-Bouzas, C; Guerra, I; Viguera, N; Moreno, J; Ibañez, E; Díez, J; Rodríguez, F; Mallabiabarrena, G; Luján, S; Gorostiaga, J; De Pablo, J L; Mendizabal, J L; Tejada, M I

    2007-12-01

    The prevalence of unique and recurrent BRCA1 and BRCA2 pathogenic mutations and unclassified variants varies among different populations. Two hundred and thirty-six breast and/or ovarian cancer patients were analysed to clarify the role of these genes in the Basque Country. We also studied 130 healthy women from the general population from the same region. Fifteen different pathological mutations were found in 16 index cases: 10 truncating mutations, 4 missense mutations and 1 splicing mutation. c.3002_3003insT and c.5788_5789delGT, both in exon 11 of BRCA2 have not previously been described. No pathological mutations were found in cases of sporadic juvenile breast cancer. There are no recurrent mutations in our population; apart from the mutation c.9254_9258del5, which appears in only two index cases. We have also found a lot of variants whose effect is unknown. From these variants, 17 have not previously been described: 6 missenses, 6 synonymous and 5 alterations in intronic regions. We would like to highlight the fact that 14.3% of patients with 3 or more cases of breast cancer in the family, and 16.7% of patients with family history of breast and ovarian cancer, present a pathological mutation in BRCA1 or BRCA2. This manuscript demonstrates that each population can have different mutations and due to this, Genetic Counselling and selection criteria must be different for each population. Furthermore, this article describes for the first time some new mutations and unclassified variants found in our population.

  9. Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil

    PubMed Central

    Palmero, Edenir Inêz; Alemar, Bárbara; Schüler-Faccini, Lavínia; Hainaut, Pierre; Moreira-Filho, Carlos Alberto; Ewald, Ingrid Petroni; dos Santos, Patricia Koehler; Ribeiro, Patricia Lisbôa Izetti; de Oliveira, Cristina Brinkmann; Kelm, Florence Le Calvez; Tavtigian, Sean; Cossio, Silvia Liliana; Giugliani, Roberto; Caleffi, Maira; Ashton-Prolla, Patricia

    2016-01-01

    Abstract In Brazil, breast cancer is a public health care problem due to its high incidence and mortality rates. In this study, we investigated the prevalence of hereditary breast cancer syndromes (HBCS) in a population-based cohort in Brazils southernmost capital, Porto Alegre. All participants answered a questionnaire about family history (FH) of breast, ovarian and colorectal cancer and those with a positive FH were invited for genetic cancer risk assessment (GCRA). If pedigree analysis was suggestive of HBCS, genetic testing of the BRCA1, BRCA2, TP53, and CHEK2 genes was offered. Of 902 women submitted to GCRA, 214 had pedigrees suggestive of HBCS. Fifty of them underwent genetic testing: 18 and 40 for BRCA1/BRCA2 and TP53 mutation screening, respectively, and 7 for CHEK2 1100delC testing. A deleterious BRCA2 mutation was identified in one of the HBOC probands and the CHEK2 1100delC mutation occurred in one of the HBCC families. No deleterious germline alterations were identified in BRCA1 or TP53. Although strict inclusion criteria and a comprehensive testing approach were used, the suspected genetic risk in these families remains unexplained. Further studies in a larger cohort are necessary to better understand the genetic component of hereditary breast cancer in Southern Brazil. PMID:27223485

  10. A cross-linker-sensitive myeloid leukemia cell line from a 2-year-old boy with severe Fanconi anemia and biallelic FANCD1/BRCA2 mutations.

    PubMed

    Meyer, Stefan; Fergusson, William D; Oostra, Anneke B; Medhurst, Annette L; Waisfisz, Quinten; de Winter, Johan P; Chen, Fei; Carr, Trevor F; Clayton-Smith, Jill; Clancy, Tara; Green, Mike; Barber, Lisa; Eden, Osborn B; Will, Andrew M; Joenje, Hans; Taylor, G Malcolm

    2005-04-01

    Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital and developmental abnormalities, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), and strong predisposition to acute myeloid leukemia (AML). In this article, we describe clinical and molecular findings in a boy with a severe FA phenotype who developed AML by the age of 2. Although he lacked a strong family history of cancer, he was subsequently shown to carry biallelic mutations in the FANCD1/BRCA2 gene. These included an IVS7 splice-site mutation, which is strongly associated with early AML in homozygous or compound heterozygous carrier status in FA-D1 patients. Myeloid leukemia cells from this patient have been maintained in culture for more than 1 year and have been designated as the SB1690CB cell line. Growth of SB1690CB is dependent on granulocyte macrophage colony stimulating factor or interleukin-3. This cell line has retained its MMC sensitivity and has undergone further spontaneous changes in the spectrum of cytogenetic aberrations compared with the primary leukemia. This is the second AML cell line derived from an FA-D1 patient and the first proof that malignant clones arising in FA patients can retain inherited MMC sensitivity. As FA-derived malignancies are normally not very responsive to treatment, this implies there are important mechanisms of acquiring correction of the cellular FA phenotype that would explain the poor chemoresponsiveness observed in FA-associated malignancies and might also play a role in the initiation and progression of cancer in the general population.

  11. Population Testing for Cancer Predisposing BRCA1/BRCA2 Mutations in the Ashkenazi-Jewish Community: A Randomized Controlled Trial

    PubMed Central

    Manchanda, Ranjit; Loggenberg, Kelly; Sanderson, Saskia; Burnell, Matthew; Wardle, Jane; Gessler, Sue; Side, Lucy; Balogun, Nyala; Desai, Rakshit; Kumar, Ajith; Dorkins, Huw; Wallis, Yvonne; Chapman, Cyril; Taylor, Rohan; Jacobs, Chris; Tomlinson, Ian; McGuire, Alistair; Beller, Uziel; Menon, Usha

    2015-01-01

    Background: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)–based testing. Methods: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population screening (PS) arm with testing those fulfilling standard FH-based clinical criteria (FH arm). Following a targeted community campaign, AJ participants older than 18 years were recruited by self-referral after pretest genetic counseling. The effects of BRCA1/2 genetic testing on acceptability, psychological impact, and quality-of-life measures were assessed by random effects regression analysis. All statistical tests were two-sided. Results: One thousand, one hundred sixty-eight AJ individuals were counseled, 1042 consented, 1034 were randomly assigned (691 women, 343 men), and 1017 were eligible for analysis. Mean age was 54.3 (SD = 14.66) years. Thirteen BRCA1/2 carriers were identified in the PS arm, nine in the FH arm. Five more carriers were detected among FH-negative FH-arm participants following study completion. There were no statistically significant differences between the FH and PS arms at seven days or three months on measures of anxiety, depression, health anxiety, distress, uncertainty, and quality-of-life. Contrast tests indicated that overall anxiety (P = .0001) and uncertainty (P = .005) associated with genetic testing decreased; positive experience scores increased (P = .0001); quality-of-life and health anxiety did not change with time. Overall, 56% of carriers did not fulfill clinical criteria for genetic testing, and the BRCA1/2 prevalence was 2.45%. Conclusion: Compared with FH-based testing, population-based genetic testing in Ashkenazi Jews doesn

  12. Ovarian cancer in BRCA1 and BRCA2 gene mutation carriers: analysis of prognostic factors and survival

    PubMed Central

    Biglia, Nicoletta; Sgandurra, Paola; Bounous, Valentina Elisabetta; Maggiorotto, Furio; Piva, Eleonora; Pivetta, Emanuele; Ponzone, Riccardo; Pasini, Barbara

    2016-01-01

    Objectives To compare clinical–pathological characteristics and outcome between sporadic ovarian cancer and ovarian cancer in patents with hereditary breast and ovarian cancer syndrome (HBOC). Methods Twenty-four patients with ovarian cancer treated between 2000 and 2009 who tested positive for BRCA1/2 mutation (BRCA+) and a control group of 64 age-matched patients with no family history of breast/ovarian cancer (controls) were enrolled. Clinical–pathological characteristics, surgical outcome, overall (OS), and progression-free survival (PFS) were compared between the two groups. Results The high-grade serous histotype was more represented in BRCA+ than in controls (70.8% versus 53.1%) (p > 0.05). BRCA+ cancers were more frequently diagnosed at stage II than controls (20.83% versus 4.69%) (p = 0.024). Radical primary surgery was performed in 70% of women in both groups, with no difference in debulking results. In patients undergoing surgery after neoadjuvant chemotherapy, in all BRCA+ patients, optimal cytoreduction was achieved (versus 70% of the controls). PFS was significantly longer for BRCA+ patients compared to controls (60 months versus 22 months; p = 0.039). No significant difference was observed in OS between BRCA+ patients and controls. Conclusions At a median follow-up time of 46 months, BRCA+ patients have a better prognosis than controls in terms of PFS. Higher chemosensitivity of BRCA+ tumours was observed. PMID:27350785

  13. Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French‐Canadian families with high risk of breast and ovarian cancer

    PubMed Central

    Simard, Jacques; Dumont, Martine; Moisan, Anne‐Marie; Gaborieau, Valérie; Vézina, Hélène; Durocher, Francine; Chiquette, Jocelyne; Plante, Marie; Avard, Denise; Bessette, Paul; Brousseau, Claire; Dorval, Michel; Godard, Béatrice; Houde, Louis; Joly, Yann; Lajoie, Marie‐Andrée; Leblanc, Gilles; Lépine, Jean; Lespérance, Bernard; Malouin, Hélène; Parboosingh, Jillian; Pichette, Roxane; Provencher, Louise; Rhéaume, Josée; Sinnett, Daniel; Samson, Carolle; Simard, Jean‐Claude; Tranchant, Martine; Voyer, Patricia; BRCAs, INHERIT; Easton, Douglas; Tavtigian, Sean V; Knoppers, Bartha‐Maria; Laframboise, Rachel; Bridge, Peter; Goldgar, David

    2007-01-01

    Background and objective In clinical settings with fixed resources allocated to predictive genetic testing for high‐risk cancer predisposition genes, optimal strategies for mutation screening programmes are critically important. These depend on the mutation spectrum found in the population under consideration and the frequency of mutations detected as a function of the personal and family history of cancer, which are both affected by the presence of founder mutations and demographic characteristics of the underlying population. The results of multistep genetic testing for mutations in BRCA1 or BRCA2 in a large series of families with breast cancer in the French‐Canadian population of Quebec, Canada are reported. Methods A total of 256 high‐risk families were ascertained from regional familial cancer clinics throughout the province of Quebec. Initially, families were tested for a panel of specific mutations known to occur in this population. Families in which no mutation was identified were then comprehensively tested. Three algorithms to predict the presence of mutations were evaluated, including the prevalence tables provided by Myriad Genetics Laboratories, the Manchester Scoring System and a logistic regression approach based on the data from this study. Results 8 of the 15 distinct mutations found in 62 BRCA1/BRCA2‐positive families had never been previously reported in this population, whereas 82% carried 1 of the 4 mutations currently observed in ⩾2 families. In the subset of 191 families in which at least 1 affected individual was tested, 29% carried a mutation. Of these 27 BRCA1‐positive and 29 BRCA2‐positive families, 48 (86%) were found to harbour a mutation detected by the initial test. Among the remaining 143 inconclusive families, all 8 families found to have a mutation after complete sequencing had Manchester Scores ⩾18. The logistic regression and Manchester Scores provided equal predictive power, and both were significantly better

  14. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.

    PubMed

    Yang, Haijuan; Jeffrey, Philip D; Miller, Julie; Kinnucan, Elspeth; Sun, Yutong; Thoma, Nicolas H; Zheng, Ning; Chen, Phang-Lang; Lee, Wen-Hwa; Pavletich, Nikola P

    2002-09-13

    Mutations in the BRCA2 (breast cancer susceptibility gene 2) tumor suppressor lead to chromosomal instability due to defects in the repair of double-strand DNA breaks (DSBs) by homologous recombination, but BRCA2's role in this process has been unclear. Here, we present the 3.1 angstrom crystal structure of a approximately 90-kilodalton BRCA2 domain bound to DSS1, which reveals three oligonucleotide-binding (OB) folds and a helix-turn-helix (HTH) motif. We also (i) demonstrate that this BRCA2 domain binds single-stranded DNA, (ii) present its 3.5 angstrom structure bound to oligo(dT)9, (iii) provide data that implicate the HTH motif in dsDNA binding, and (iv) show that BRCA2 stimulates RAD51-mediated recombination in vitro. These findings establish that BRCA2 functions directly in homologous recombination and provide a structural and biochemical basis for understanding the loss of recombination-mediated DSB repair in BRCA2-associated cancers.

  15. Murine Brca2: Sequence, map position, and expression pattern

    SciTech Connect

    Sharan, S.K.; Bradley, A.

    1997-03-01

    Mutations in the human BRCA2 gene are responsible for about 45% of hereditary early onset breast cancer. Recently, the human BRCA2 gene was cloned, and several germline mutations were identified. Here we describe the cloning of the mouse homologue of BRCA2. The mouse cDNA sequence predicts a 3328-amino-acid Brca2 protein, 90 amino acids shorter than the human protein. The overall identity between the mouse and the human proteins is 59%, while the similarity is 72%. At the nucleotide level the homology is 74%. By comparing the amino acid sequences of the two homologues we have identified five highly conserved novel domains that may be functionally significant. Brca2 has been mapped to the distal end of mouse chromosome 5, a region of the mouse genome that contains other genes that also map to human chromosome 13q12-q13, confirming the conservation of this linkage group between the two species. Expression of Brca2 was detected in midgestation embryos and adult testis, thymus, and ovary. 21 refs., 5 figs.

  16. Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies

    PubMed Central

    Ding, Xia; Chaudhuri, Arnab Ray; Callen, Elsa; Pang, Yan; Biswas, Kajal; Klarmann, Kimberly D.; Martin, Betty K.; Burkett, Sandra; Cleveland, Linda; Stauffer, Stacey; Sullivan, Teresa; Dewan, Aashish; Marks, Hanna; Tubbs, Anthony T.; Wong, Nancy; Buehler, Eugen; Akagi, Keiko; Martin, Scott E.; Keller, Jonathan R.; Nussenzweig, André; Sharan, Shyam K.

    2016-01-01

    Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. BRCA1- and BRCA2-mutated cells, which are homologous recombination (HR) deficient, are hypersensitive to PARPi through the mechanism of synthetic lethality. Here we examine the effect of PARPi on HR-proficient cells. Olaparib pretreatment, PARP1 knockdown or Parp1 heterozygosity of Brca2cko/ko mouse embryonic stem cells (mESCs), carrying a null (ko) and a conditional (cko) allele of Brca2, results in viable Brca2ko/ko cells. PARP1 deficiency does not restore HR in Brca2ko/ko cells, but protects stalled replication forks from MRE11-mediated degradation through its impaired recruitment. The functional consequence of Parp1 heterozygosity on BRCA2 loss is demonstrated by a significant increase in tumorigenesis in Brca2cko/cko mice. Thus, while olaparib efficiently kills BRCA2-deficient cells, we demonstrate that it can also contribute to the synthetic viability if PARP is inhibited before BRCA2 loss. PMID:27498558

  17. Quantitative analysis of γ-H2AX and p53 nuclear expression levels in ovarian and fallopian tube epithelium from risk-reducing salpingo-oophorectomies in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Staff, Synnöve; Tolonen, Teemu; Laasanen, Satu-Leena; Mecklin, Jukka-Pekka; Isola, Jorma; Mäenpää, Johanna

    2014-05-01

    Mutations in BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Increased lifetime ovarian cancer risk among BRCA1/BRCA2 mutation carriers can be substantially decreased by risk-reducing salpingo-oophorectomy (RRSO), which also provides material for molecular research on early pathogenesis of serous ovarian cancer. RRSO studies have suggested fallopian tube as a primary site of serous high-grade ovarian cancer. In this study, the nuclear expression levels of γ-H2AX and p53 using immunohistochemical (IHC) study was quantitatively assessed in ovarian and fallopian tube epithelium derived from RRSOs in 29 BRCA1 and BRCA2 mutation carriers and in 1 patient with a strong family history of breast and ovarian cancer but showing an unknown BRCA status. Both p53 and γ-H2AX nuclear staining levels were significantly higher in BRCA1/2 mutation-positive fallopian tube epithelium compared with the control fallopian tube epithelium (P<0.006 and P=0.011, respectively). Nuclear expression levels of p53 and γ-H2AX were similar between the BRCA1/2 mutation-positive ovarian epithelium and controls. Both γ-H2AX and p53 showed significantly higher nuclear expression levels in BRCA1/2 mutation-positive fallopian tube epithelium compared with BRCA1/2 mutation-positive ovarian epithelium (P<0.0001 and P<0.0001, respectively). BRCA1/2 mutation-positive fallopian tube epithelium showed a positive correlation between the γ-H2AX and p53 nuclear expression levels (Pearson r=0.508, P=0.003). Our results of quantitative nuclear p53 and γ-H2AX expression levels in ovarian and fallopian tube epithelium derived from RRSO in high-risk patients support the previously suggested role of fallopian tube epithelium serving as a possible site of initial serous ovarian carcinogenesis.

  18. The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population

    PubMed Central

    2011-01-01

    Background The BRCA1 and BRCA2 mutation spectrum and mutation detection rates according to different family histories were investigated in 521 subjects from 322 unrelated Slovenian cancer families with breast and/or ovarian cancer. Methods The BRCA1 and BRCA2 genes were screened using DGGE, PTT, HRM, MLPA and direct sequencing. Results Eighteen different mutations were found in BRCA1 and 13 in BRCA2 gene. Mutations in one or other gene were found in 96 unrelated families. The mutation detection rates were the highest in the families with at least one breast and at least one ovarian cancer - 42% for BRCA1 and 8% for BRCA2. The mutation detection rate observed in the families with at least two breast cancers with disease onset before the age of 50 years and no ovarian cancer was 23% for BRCA1 and 13% for BRCA2. The mutation detection rate in the families with at least two breast cancers and only one with the disease onset before the age of 50 years was 11% for BRCA1 and 8% for BRCA2. In the families with at least two breast cancers, all of them with disease onset over the age of 50 years, the detection rate was 5% for BRCA2 and 0% for BRCA1. Conclusion Among the mutations detected in Slovenian population, 5 mutations in BRCA1 and 4 mutations in BRCA2 have not been described in other populations until now. The most frequent mutations in our population were c.181T > G, c.1687C > T, c.5266dupC and c.844_850dupTCATTAC in BRCA1 gene and c.7806-2A > G, c.5291C > G and c.3978insTGCT in BRCA2 gene (detected in 69% of BRCA1 and BRCA2 positive families). PMID:21232165

  19. Multifactorial Likelihood Assessment of BRCA1 and BRCA2 Missense Variants Confirms That BRCA1:c.122A>G(p.His41Arg) Is a Pathogenic Mutation

    PubMed Central

    Whiley, Phillip J.; Parsons, Michael T.; Leary, Jennifer; Tucker, Kathy; Warwick, Linda; Dopita, Belinda; Thorne, Heather; Lakhani, Sunil R.; Goldgar, David E.; Brown, Melissa A.; Spurdle, Amanda B.

    2014-01-01

    Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg) RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1), nine were likely not pathogenic (Class 2), and one was uncertain (Class 3).These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies. PMID:24489791

  20. Prognosis of probability of BRCA1 and BRCA2 mutations carriage in women with compromised family history of breast and/or ovarian cancer.

    PubMed

    Rybchenko, L A; Bychkova, A M; Skyban, G V; Klymenko, S V

    2013-01-01

    Obtjazhenist' simejnogo anamnezu shhodo raku molochnoi' zalozy ta/abo raku jajechnykiv mozhe svidchyty pro nosijstvo mutacii' v BRCA1 ta BRCA2 genah. Meta: ocinyty ta porivnjaty mozhlyvosti Manchesters'koi' bal'noi' systemy, algorytmu Penn II ta Myriad na indyvidual'nomu rivni vidriznjaty pacijentiv z mutacijeju BRCA1/2 ta osib bez mutantnyh alelej sered ukrai'ns'kyh zhinok z rannim rozvytkom raku molochnoi' zalozy ta/abo obtjazhenym simejnym anamnezom shhodo raku molochnoi' zalozy ta/abo raku jajechnykiv. Material ta metody doslidzhennja. Materialom doslidzhennja sluguvaly rezul'taty genealogichnogo, molekuljarno-genetychnogo ta kliniko-morfologichnogo obstezhennja 44 osib, hvoryh na rak molochnoi' zalozy, z rannim rozvytkom zahvorjuvannja abo z obtjazhenym simejnym anamnezom shhodo onkologichnoi' patologii' molochnoi' zalozy ta/abo jajechnykiv. Vyznachennja najbil'sh imovirnyh nosii'v mutacij BRCA1 i BRCA2 sered obstezhenyh zhinok provodyly za dopomogoju tr'oh vyshhezgadanyh algorytmiv. Rezul'taty ta vysnovky. Manchesters'ka bal'na systema maje krashhu zdatnist' na indyvidual'nomu rivni vidriznjaty pacijentiv z mutacijeju ta osib bez mutantnyh alelej. Ploshha pid kryvoju Manchesters'koi' bal'noi' systemy skladaje 0,84, Penn II – 0,66, Myriad – 0,68.

  1. Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi Anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.

    PubMed

    García, María J; Fernández, Victoria; Osorio, Ana; Barroso, Alicia; Fernández, Fernando; Urioste, Miguel; Benítez, Javier

    2009-11-01

    Fanconi Anemia (FA) is a rare recessive syndrome characterized by cellular hypersensitivity to DNA-cross-linking agents. To date, 13 FA complementation groups have been described and all 13 genes associated to each of these groups have been currently identified. Three of the known FA genes are also high-risk (FANCD1/BRCA2) or moderate-risk (FANCN/PALB2 and FANCJ/BRIP1) breast cancer susceptibility genes, which makes all members of the FA pathway particularly attractive breast cancer candidate genes. Most FA genes have been screened for mutations in breast cancer families negative for BRCA1/2 mutations but the role of FANCL, FANCM and the recently identified FANCI has not been evaluated to date. This fact and novel data sustaining greater functional relevance of the three genes within the FA pathway prompted us to scrutinize all coding sequences and splicing sites of FANCI, FANCL and FANCM in 95 BRCA1/2-negative index cases from Spanish high-risk breast cancer families. We identified 68 sequence variants of which 24 were coding and 44 non-coding. Six exonic and 26 non-coding variants had not been described previously. None of the coding changes caused clearly pathogenic changes and computational analysis of all non-described intronic variants did not revealed major impact in splicing. With the present study, all known FA genes have been evaluated within the context of breast cancer high-risk predisposition. Our results rule out a major role of FANCI, FANCL and FANCM in familial breast cancer susceptibility, suggesting that among the 13 known FA genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.

  2. Genetic heterogeneity in hereditary breast cancer: Role of BRCA1 and BRCA2

    SciTech Connect

    Rebbeck, T.R.; Couch, F.J.; Kant, J.

    1996-09-01

    The common hereditary forms of breast cancer have been largely attributed to the inheritance of mutations in the BRCA1 or BRCA2 genes. However, it is not yet clear what proportion of hereditary breast cancer is explained by BRCA1 and BRCA2 or by some other unidentified susceptibility gene(s). We describe the proportion of hereditary breast cancer explained by BRCA1 or BRCA2 in a sample of North American hereditary breast cancers and assess the evidence for additional susceptibility genes that may confer hereditary breast or ovarian cancer risk. Twenty-three families were identified through two high-risk breast cancer research programs. Genetic analysis was undertaken to establish linkage between the breast or ovarian cancer cases and markers on chromosomes 17q (BRCA1) and 13q (BRCA2). Mutation analysis in the BRCA1 and BRCA2 genes was also undertaken in all families. The pattern of hereditary cancer in 14 (61%) of the 23 families studied was attributed to BRCA1 by a combination of linkage and mutation analyses. No families were attributed to BRCA2. Five families (22%) provided evidence against linkage to both BRCA1 and BRCA2. No BRCA1 or BRCA2 mutations were detected in these five families. The BRCA1 or BRCA2 status of four families (17%) could not be determined. BRCA1 and BRCA2 probably explain the majority of hereditary breast cancer that exists in the North American population. However, one or more additional genes may yet be found that explain some proportion of hereditary breast cancer. 19 refs., 1 fig., 3 tabs.

  3. Interaction with PALB2 Is Essential for Maintenance of Genomic Integrity by BRCA2

    PubMed Central

    Hartford, Suzanne A.; Chittela, Rajanikant; Ding, Xia; Martin, Betty; Burkett, Sandra; Haines, Diana C.; Southon, Eileen; Tessarollo, Lino; Sharan, Shyam K.

    2016-01-01

    Human breast cancer susceptibility gene, BRCA2, encodes a 3418-amino acid protein that is essential for maintaining genomic integrity. Among the proteins that physically interact with BRCA2, Partner and Localizer of BRCA2 (PALB2), which binds to the N-terminal region of BRCA2, is vital for its function by facilitating its subnuclear localization. A functional redundancy has been reported between this N-terminal PALB2-binding domain and the C-terminal DNA-binding domain of BRCA2, which undermines the relevance of the interaction between these two proteins. Here, we describe a genetic approach to examine the functional significance of the interaction between BRCA2 and PALB2 by generating a knock-in mouse model of Brca2 carrying a single amino acid change (Gly25Arg, Brca2G25R) that disrupts this interaction. In addition, we have combined Brca2G25R homozygosity as well as hemizygosity with Palb2 and Trp53 heterozygosity to generate an array of genotypically and phenotypically distinct mouse models. Our findings reveal defects in body size, fertility, meiotic progression, and genome stability, as well as increased tumor susceptibility in these mice. The severity of the phenotype increased with a decrease in the interaction between BRCA2 and PALB2, highlighting the significance of this interaction. In addition, our findings also demonstrate that hypomorphic mutations such as Brca2G25R have the potential to be more detrimental than the functionally null alleles by increasing genomic instability to a level that induces tumorigenesis, rather than apoptosis. PMID:27490902

  4. Development of Anti-Cancer Therapeutics That Modulate the RAD51-BRCA2 Complex

    DTIC Science & Technology

    2005-03-01

    the Rad5 I -Brca2 interaction. 14. SUBJECT TERMS 15. NUMBER OF PAGES BRCA2, RAD51 Recombination 47 16. PRICE CODE 17. SECURITY CLASSIFICATION 18 ...randomly mutated baits for their interaction with Rad54, Rad5 1, the BRC motif, and Brca2 exon 27. We have isolated 18 mutations in Rad51 that impair...24 59 75 0 18 93 Mitomycin C 30 93 4.60 13 66 30 96 27 14 I 42 ’Calculated without chromatid gaps. b’Gaps" defined as discontinuities smaller than the

  5. BRCA1 and BRCA2 genetic test in high risk patients and families: counselling and management.

    PubMed

    Marchina, Eleonora; Fontana, Maria Grazia; Speziani, Michela; Salvi, Alessandro; Ricca, Giuseppe; Di Lorenzo, Diego; Gervasi, Maria; Caimi, Luigi; Barlati, Sergio

    2010-12-01

    Hereditary breast cancer accounts for 5-10% of all cases of breast cancer and 10-15% of ovarian cancer and is characterised by dominant inheritance, early onset, the severity of the disease and bilaterality. About 30% of cases with hereditary breast and ovarian cancer have mutations in the BRCA1 and BRCA2 genes. Women with a mutation in the BRCA1 gene have a 80-90% lifetime risk of developing breast cancer, and 40-65% chance of developing ovarian cancer. Most studies carried out throughout the world indicate that the prevalence of BRCA1 and BRCA2 mutation is lower than originally suggested by early studies on large families with several affected members. Studies performed in Italy have reported different prevalence of BRCA1 and BRCA2 mutations, probably due to different selection criteria and to the variability of the techniques used. In this study, we performed a screening of BRCA1 and BRCA2 in families from northern Italy with familial recurrence of breast cancer or ovarian cancer in which the individual risk of patients of being carriers of BRCA1 and BRCA2 mutation was evaluated using BRCAPRO (CAGene) software. We enrolled 27 patients of 101 unrelated families selected when they fulfilled the inclusion criteria of the American Society of Clinical Oncology (ASCO). Specific risk evaluation, genetic test administration if needed, and discussion of the results were offered during multi-disciplinary genetic, surgical and psychological counselling. Seven probands (35%) found BRCA1/2 sequence variation carriers; no BRCA1 and BRCA2 mutations were detected in the remaining 13 probands. Two (15%) patients had BRCA1 mutations and 5 (25%) patients had BRCA2 mutations. In the latter case, BRCA2 delA 9158fs+29stop mutation in exon 22, never previously described and a new sequence variation (T703N) in exon 11 were identified.

  6. Functional analysis of human BRCA2 variants using a mouse embryonic stem cell-based assay.

    PubMed

    Kuznetsov, Sergey G; Chang, Suhwan; Sharan, Shyam K

    2010-01-01

    We describe here a comprehensive and reliable assay to test the functional significance of variants of unknown clinical significance (VUS) identified in the human breast cancer susceptibility gene, BRCA2. The assay is based on the ability of human BRCA2 to complement the loss of endogenous Brca2 in mouse embryonic stem cells. The procedure involves generation of a desired mutation in BRCA2 present in a bacterial artificial chromosome (BAC) and the introduction of the BAC into ES cells engineered for the assay. These ES cells have one null and one conditional allele of Brca2. First, the effect of the BRCA2 variants on the viability of ES cells is tested by Cre-mediated deletion of the conditional allele. Subsequently, variants that result in viable ES cells are examined for their effect on known functions of BRCA2 using a variety of functional assays such as sensitivity to genotoxic agents, in vivo and in vitro proliferation, effect on homologous recombination and genomic stability. The method described herein allows for the analysis of three to five sequence variants within 2-3 months. This approach can also be used for functional analysis of variants identified in other human disease genes that result in a phenotype detectable in ES cells.

  7. APRIN is a cell cycle specific BRCA2-interacting protein required for genome integrity and a predictor of outcome after chemotherapy in breast cancer

    PubMed Central

    Brough, Rachel; Bajrami, Ilirjana; Vatcheva, Radost; Natrajan, Rachael; Reis-Filho, Jorge S; Lord, Christopher J; Ashworth, Alan

    2012-01-01

    Mutations in BRCA2 confer an increased risk of cancer development, at least in part because the BRCA2 protein is required for the maintenance of genomic integrity. Here, we use proteomic profiling to identify APRIN (PDS5B), a cohesion-associated protein, as a BRCA2-associated protein. After exposure of cells to hydroxyurea or aphidicolin, APRIN and other cohesin components associate with BRCA2 in early S-phase. We demonstrate that APRIN expression is required for the normal response to DNA-damaging agents, the nuclear localisation of RAD51 and BRCA2 and efficient homologous recombination. The clinical significance of these findings is indicated by the observation that the BRCA2/APRIN interaction is compromised by BRCA2 missense variants of previously unknown significance and that APRIN expression levels are associated with histological grade in breast cancer and the outcome of breast cancer patients treated with DNA-damaging chemotherapy. PMID:22293751

  8. Large genomic rearrangement of BRCA1 and BRCA2 genes in familial breast cancer patients in Korea.

    PubMed

    Cho, Ja Young; Cho, Dae-Yeon; Ahn, Sei Hyun; Choi, Su-Youn; Shin, Inkyung; Park, Hyun Gyu; Lee, Jong Won; Kim, Hee Jeong; Yu, Jong Han; Ko, Beom Seok; Ku, Bo Kyung; Son, Byung Ho

    2014-06-01

    We screened large genomic rearrangements of the BRCA1 and BRCA2 genes in Korean, familial breast cancer patients. Multiplex ligation-dependent probe amplification assay was used to identify BRCA1 and BRCA2 genomic rearrangements in 226 Korean familial breast cancer patients with risk factors for BRCA1 and BRCA2 mutations, who previously tested negative for point mutations in the two genes. We identified only one large deletion (c.4186-1593_4676-1465del) in BRCA1. No large rearrangements were found in BRCA2. Our result indicates that large genomic rearrangement in the BRCA1 and BRCA2 genes does not seem like a major determinant of breast cancer susceptibility in the Korean population. A large-scale study needs to validate our result in Korea.

  9. Aceruloplasminemia in an asymptomatic patient with a new mutation. Diagnosis and family genetic analysis.

    PubMed

    Pérez-Aguilar, Fernando; Burguera, Juan A; Benlloch, Salvador; Berenguer, Marina; Rayón, Jose M

    2005-06-01

    A 39-year-old asymptomatic man showed elevated serum ferritin levels, mild hypertransaminasemia and serum ceruloplasmin almost undetectable. There was histological iron accumulation within the hepatocytes and also in the central nervous system (MRI). A genetic analysis revealed a new missense mutation in the ceruloplasmin gene. Two of the other four siblings were also affected by this mutation.

  10. Arabidopsis BRCA2 and RAD51 proteins are specifically involved in defense gene transcription during plant immune responses

    PubMed Central

    Wang, Shui; Durrant, Wendy E.; Song, Junqi; Spivey, Natalie W.; Dong, Xinnian

    2010-01-01

    Systemic acquired resistance (SAR) is a plant immune response associated with both transcriptional reprogramming and increased homologous DNA recombination (HR). SNI1 is a negative regulator of SAR and HR, as indicated by the increased basal expression of defense genes and HR in sni1. We found that the sni1 phenotypes are rescued by mutations in BREAST CANCER 2 (BRCA2). In humans, BRCA2 is a mediator of RAD51 in pairing of homologous DNA. Mutations in BRCA2 cause predisposition to breast/ovarian cancers; however, the role of the BRCA2–RAD51 complex in transcriptional regulation remains unclear. In Arabidopsis, both brca2 and rad51 were found to be hypersusceptible not only to genotoxic substances, but also to pathogen infections. A whole-genome microarray analysis showed that downstream of NPR1, BRCA2A is a major regulator of defense-related gene transcription. ChIP demonstrated that RAD51 is specifically recruited to the promoters of defense genes during SAR. This recruitment is dependent on the SAR signal salicylic acid (SA) and on the function of BRCA2. This study provides the molecular evidence showing that the BRCA2–RAD51 complex, known for its function in HR, also plays a direct and specific role in transcription regulation during plant immune responses. PMID:21149701

  11. Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2

    PubMed Central

    Rytelewski, Mateusz; Vareki, Saman Maleki; Mangala, Lingegowda S.; Romanow, Larissa; Jiang, Dahai; Pradeep, Sunila; Rodriguez-Aguayo, Christian; Lopez-Berestein, Gabriel; Figueredo, Rene; Ferguson, Peter J.; Vincent, Mark; Sood, Anil K.; Koropatnick, James D.

    2016-01-01

    Human tumor heterogeneity promotes therapeutic failure by increasing the likelihood of resistant cell subpopulations. The PARP-1 inhibitor olaparib is approved for use in BRCA-mutated ovarian cancers but BRCA2-reversion mutations lead to functional homologous recombination repair (HRR) and olaparib resistance. To overcome that resistance and expand use of PARP1 inhibition to cancers with functional HRR, we developed an antisense strategy to render the majority of tumor cells in a population BRCA2-deficient. We predicted that this strategy would render HRR-proficient tumor cells sensitive to olaparib and prevent emergence of resistance in a tumor cell population heterogeneous for HRR proficiency. We report that BRCA2 downregulation sensitized multiple human tumor cell lines (but not non-cancer human kidney cells) to olaparib and, combined with olaparib, increased aneuploidy and chromosomal translocations in human tumor cells. In a mixed HRR-proficient and HRR-deficient cell population, olaparib monotherapy allowed outgrowth of HRR-proficient cells resistant to subsequent olaparib treatment. Combined BRCA2 inhibition and olaparib treatment prevented selection of HRR-proficient cells and inhibited proliferation of the entire population. Treatment with BRCA2 siRNA and olaparib decreased ovarian xenograft growth in mice more effectively than either treatment alone. In vivo use of BRCA2 antisense oligonucleotides may be a viable option to expand clinical use of olaparib and prevent resistance. PMID:26959114

  12. BRCA1/BRCA2 mutation status and analysis of cancer family history in participants of the Royal Marsden Hospital tamoxifen chemoprevention trial.

    PubMed

    Kote-Jarai, Zsofia; Powles, Trevor J; Mitchell, Gillian; Tidy, Alwynne; Ashley, Sue; Easton, Douglas; Assersohn, Laura; Sodha, Nayanta; Salter, Janine; Gusterson, Barry; Dowsett, Mitch; Eeles, Rosalind

    2007-03-18

    We have analysed the pedigrees of all 70 women who developed cancer in the Royal Marsden Hospital (RMH) tamoxifen chemoprevention trial, using the Claus model, to assess breast cancer susceptibility heterozygote risk (HR) and screened the entire coding regions of BRCA1 and 2 genes in 62 of these cases. We found a reduced incidence of breast cancers developing on tamoxifen in women who have a lower HR, but not in women with higher HR. There were too few BRCA1/2 mutations (4 cases) to be able to determine the efficacy of tamoxifen by BRCA status. Immunohistochemical analysis showed a significantly lower frequency of median ER (p=0.03) in the cancers developing in tamoxifen-treated patients. These results suggest that tamoxifen is less likely to be effective at reducing breast cancers which are ER negative and also in some individuals at higher HR.

  13. Characterizing a Rat Brca2 Knockout Model

    DTIC Science & Technology

    2007-05-01

    this treatment (Figure 2b). Aspermatogenesis Meiosis in Brca2/ rats proceeds normally through leptotene and early zygotene (Figure 3a) with 40...Zygotene Late Zygotene Scp3Scp3 Scp3 Scp3 Scp1 CREST CRESTCREST Merge a b Figure 3 (a) Meiosis in Brca2/ spermatocytes does not progress beyond late...control of noncrossover and crossover recombination during meiosis . Cell 106: 47–57. Barlow C, Liyanage M, Moens PB, Tarsounas M, Nagashima K, Brown K

  14. Inactivation of BRCA2 in human cancer cells identifies a subset of tumors with enhanced sensitivity towards death receptormediated apoptosis

    PubMed Central

    De Toni, Enrico N.; Ziesch, Andreas; Rizzani, Antonia; Török, Helga-Paula; Hocke, Sandra; Lü, Shuai; Wang, Shao-Chun; Hucl, Tomas; Göke, Burkhard; Bruns, Christiane; Gallmeier, Eike

    2016-01-01

    Purpose DNA repair defects due to detrimental BRCA2-mutations confer increased susceptibility towards DNA interstrand-crosslinking (ICL) agents and define patient subpopulations for individualized genotype-based cancer therapy. However, due to the side effects of these drugs, there is a need to identify additional agents, which could be used alone or in combination with ICL-agents. Therefore, we investigated whether BRCA2-mutations might also increase the sensitivity towards TRAIL-receptors (TRAIL-R)-targeting compounds. Experimental design Two independent model systems were applied: a BRCA2 gene knockout and a BRCA2 gene complementation model. The effects of TRAIL-R-targeting compounds and ICL-agents on cell viability, apoptosis and cell cycle distribution were compared in BRCA2-proficient versus-deficient cancer cells in vitro. In addition, the effects of the TRAIL-R2-targeting antibody LBY135 were assessed in vivo using a murine tumor xenograft model. Results BRCA2-deficient cancer cells displayed an increased sensitivity towards TRAIL-R-targeting agents. These effects exceeded and were mechanistically distinguishable from the well-established effects of ICL-agents. In vitro, ICL-agents expectedly induced an early cell cycle arrest followed by delayed apoptosis, whereas TRAIL-R-targeting compounds caused early apoptosis without prior cell cycle arrest. In vivo, treatment with LBY135 significantly reduced the tumor growth of BRCA2-deficient cancer cells in a xenograft model. Conclusions BRCA2 mutations strongly increase the in vitro- and in vivo-sensitivity of cancer cells towards TRAIL-R-mediated apoptosis. This effect is mechanistically distinguishable from the well-established ICL-hypersensitivity of BRCA2-deficient cells. Our study thus defines a new genetic subpopulation of cancers susceptible towards TRAIL-R-targeting compounds, which could facilitate novel therapeutic approaches for patients with BRCA2-deficient tumors. PMID:26843614

  15. Adjuvant radiotherapy for primary breast cancer in BRCA1 and BRCA2 mutation carriers and risk of contralateral breast cancer with special attention to patients irradiated at younger age.

    PubMed

    Drooger, Jan; Akdeniz, Delal; Pignol, Jean-Philippe; Koppert, Linetta B; McCool, Danielle; Seynaeve, Caroline M; Hooning, Maartje J; Jager, Agnes

    2015-11-01

    The purpose of this study was to estimate the influence of adjuvant radiotherapy for primary breast cancer (BC) on the risk of contralateral BC (CBC) in BRCA1 or BRCA2 (BRCA1/2) mutation carriers, with special attention to patients irradiated at age younger than 40 years. Additionally, tendencies in locoregional treatments and rates of contralateral risk-reducing mastectomy over time were explored. In this retrospective cohort study, 691 BRCA1/2-associated BC patients treated between 1980 and 2013 were followed from diagnosis until CBC or censoring event including ipsilateral BC recurrence, distant metastasis, contralateral risk-reducing mastectomy, other invasive cancer diagnosis, death, or loss to follow up. Hazard ratios (HR) for CBC associated with radiotherapy were estimated using Cox regression. Median follow-up time was 8.6 years [range 0.3–34.3 years]. No association between radiotherapy for primary BC and risk of CBC was found, neither in the total population (HR 0.82, 95 % CI 0.45–1.49) nor in the subgroup of patients younger than 40 years at primary diagnosis (HR 1.36, 95 % CI 0.60–3.09). During follow-up, the number of patients at risk decreased substantially since a large proportion of patients were censored after contralateral risk-reducing mastectomy or BC recurrence. Over the years, increasing preference for mastectomy without radiotherapy compared to breast-conserving surgery with radiotherapy was found ranging from less than 30 % in 1995 to almost 50 % after 2010. The rate of contralateral risk-reducing mastectomy increased over the years from less than 40 % in 1995 to more than 60 % after 2010. In this cohort of BRCA1/2-associated BC patients, no association between radiotherapy for primary BC and risk of CBC was observed in the total group, nor in the patients irradiated before the age of 40 years. The number of patients at risk after 10 and 15 years of follow-up, however, was too small to definitively exclude harmful effects of adjuvant

  16. BRCA1 and BRCA2: Cancer Risk and Genetic Testing

    MedlinePlus

    ... BRCA2 genetic test result mean? What does a negative BRCA1 or BRCA2 test result mean? What does ... The medical implications of a positive or a negative test result The possibility that a test result ...

  17. Cycling with BRCA2 from DNA repair to mitosis

    SciTech Connect

    Lee, Hyunsook

    2014-11-15

    Genetic integrity in proliferating cells is guaranteed by the harmony of DNA replication, appropriate DNA repair, and segregation of the duplicated genome. Breast cancer susceptibility gene BRCA2 is a unique tumor suppressor that is involved in all three processes. Hence, it is critical in genome maintenance. The functions of BRCA2 in DNA repair and homology-directed recombination (HDR) have been reviewed numerous times. Here, I will briefly go through the functions of BRCA2 in HDR and focus on the emerging roles of BRCA2 in telomere homeostasis and mitosis, then discuss how BRCA2 exerts distinct functions in a cell-cycle specific manner in the maintenance of genomic integrity. - Highlights: • BRCA2 is a multifaceted tumor suppressor and is crucial in genetic integrity. • BRCA2 exerts distinct functions in cell cycle-specific manner. • Mitotic kinases regulate diverse functions of BRCA2 in mitosis and cytokinesis.

  18. BRCA1 and BRCA2 rearrangements in Brazilian individuals with Hereditary Breast and Ovarian Cancer Syndrome.

    PubMed

    Ewald, Ingrid Petroni; Cossio, Silvia Liliana; Palmero, Edenir Inez; Pinheiro, Manuela; Nascimento, Ivana Lucia de Oliveira; Machado, Taisa Manuela Bonfim; Sandes, Kiyoko Abe; Toralles, Betânia; Garicochea, Bernardo; Izetti, Patricia; Pereira, Maria Luiza Saraiva; Bock, Hugo; Vargas, Fernando Regla; Moreira, Miguel Ângelo Martins; Peixoto, Ana; Teixeira, Manuel R; Ashton-Prolla, Patricia

    2016-01-01

    Approximately 5-10% of breast cancers are caused by germline mutations in high penetrance predisposition genes. Among these, BRCA1 and BRCA2, which are associated with the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, are the most frequently affected genes. Recent studies confirm that gene rearrangements, especially in BRCA1, are responsible for a significant proportion of mutations in certain populations. In this study we determined the prevalence of BRCA rearrangements in 145 unrelated Brazilian individuals at risk for HBOC syndrome who had not been previously tested for BRCA mutations. Using Multiplex Ligation-dependent Probe Amplification (MLPA) and a specific PCR-based protocol to identify a Portuguese founder BRCA2 mutation, we identified two (1,4%) individuals with germline BRCA1 rearrangements (c.547+240_5193+178del and c.4675+467_5075-990del) and three probands with the c.156_157insAlu founder BRCA2 rearrangement. Furthermore, two families with false positive MLPA results were shown to carry a deleterious point mutation at the probe binding site. This study comprises the largest Brazilian series of HBOC families tested for BRCA1 and BRCA2 rearrangements to date and includes patients from three regions of the country. The overall observed rearrangement frequency of 3.44% indicates that rearrangements are relatively uncommon in the admixed population of Brazil.

  19. BRCA1 and BRCA2 rearrangements in Brazilian individuals with Hereditary Breast and Ovarian Cancer Syndrome

    PubMed Central

    Ewald, Ingrid Petroni; Cossio, Silvia Liliana; Palmero, Edenir Inez; Pinheiro, Manuela; Nascimento, Ivana Lucia de Oliveira; Machado, Taisa Manuela Bonfim; Sandes, Kiyoko Abe; Toralles, Betânia; Garicochea, Bernardo; Izetti, Patricia; Pereira, Maria Luiza Saraiva; Bock, Hugo; Vargas, Fernando Regla; Moreira, Miguel Ângelo Martins; Peixoto, Ana; Teixeira, Manuel R.; Ashton-Prolla, Patricia

    2016-01-01

    Abstract Approximately 5-10% of breast cancers are caused by germline mutations in high penetrance predisposition genes. Among these, BRCA1 and BRCA2, which are associated with the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, are the most frequently affected genes. Recent studies confirm that gene rearrangements, especially in BRCA1, are responsible for a significant proportion of mutations in certain populations. In this study we determined the prevalence of BRCA rearrangements in 145 unrelated Brazilian individuals at risk for HBOC syndrome who had not been previously tested for BRCA mutations. Using Multiplex Ligation-dependent Probe Amplification (MLPA) and a specific PCR-based protocol to identify a Portuguese founder BRCA2 mutation, we identified two (1,4%) individuals with germline BRCA1 rearrangements (c.547+240_5193+178del and c.4675+467_5075-990del) and three probands with the c.156_157insAlu founder BRCA2 rearrangement. Furthermore, two families with false positive MLPA results were shown to carry a deleterious point mutation at the probe binding site. This study comprises the largest Brazilian series of HBOC families tested for BRCA1 and BRCA2 rearrangements to date and includes patients from three regions of the country. The overall observed rearrangement frequency of 3.44% indicates that rearrangements are relatively uncommon in the admixed population of Brazil. PMID:27303907

  20. Double Heterozygosity of BRCA2 and STK11 in Familial Breast Cancer Detected by Exome Sequencing

    PubMed Central

    ATAEI-KACHOUEI, Mojgan; NADAF, Javad; AKBARI, Mohammad Taghi; ATRI, Morteza; MAJEWSKI, Jacek; RIAZALHOSSEINI, Yasser; GARSHASBI, Masoud

    2015-01-01

    Background: Germ-line mutations of BRCA1 and BRCA2 genes are responsible for approximately 25–30% of dominantly inherited familial breast cancers; still a big part of genetic component is unknown. The aim of this study was to investigate genetic causes of familial breast cancer in a pedigree with recessive pattern of inheritance. Methods: We applied exome sequencing as a useful approach in heterogeneous diseases gene identification in present study for familial breast cancer. Sanger sequencing was applied for validation and segregation analysis of mutations. Results: Here, we describe a family with three affected sisters of early-onset invasive ductal carcinoma due to heterozygous frame shift mutation rs80359352 in BRCA2 gene as the first report in Iranian patients in association with a novel missense SNP of STK11 (p.S422G). These mutations are inherited from their normal father. Conclusion: Despite apparent recessive pattern of inheritance a dominant gene (here BRCA2) can be involved in pathogenesis of hereditary breast cancer which can be explained by incomplete penetrance of BRCA2 mutations. PMID:26576347

  1. BRCA1 and BRCA2 gene testing

    MedlinePlus

    ... Search Search MedlinePlus GO GO About MedlinePlus Site Map FAQs Customer Support Health Topics Drugs & Supplements Videos & Tools Español You Are Here: Home → Medical Encyclopedia → BRCA1 and BRCA2 gene testing URL of this page: //medlineplus.gov/ency/ ...

  2. A Rare Truncating BRCA2 Variant and Genetic Susceptibility to Upper Aerodigestive Tract Cancer

    PubMed Central

    Delahaye-Sourdeix, Manon; Anantharaman, Devasena; Timofeeva, Maria N.; Gaborieau, Valérie; Chabrier, Amélie; Vallée, Maxime P.; Lagiou, Pagona; Holcátová, Ivana; Richiardi, Lorenzo; Kjaerheim, Kristina; Agudo, Antonio; Castellsagué, Xavier; Macfarlane, Tatiana V.; Barzan, Luigi; Canova, Cristina; Thakker, Nalin S.; Conway, David I.; Znaor, Ariana; Healy, Claire M.; Ahrens, Wolfgang; Zaridze, David; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Fabianova, Eleonora; Mates, Ioan Nicolae; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Curado, Maria Paula; Koifman, Sergio; Menezes, Ana; Wünsch-Filho, Victor; Eluf-Neto, José; Boffetta, Paolo; Fernández Garrote, Leticia; Polesel, Jerry; Lener, Marcin; Jaworowska, Ewa; Lubiński, Jan; Boccia, Stefania; Rajkumar, Thangarajan; Samant, Tanuja A.; Mahimkar, Manoj B.; Matsuo, Keitaro; Franceschi, Silvia; Byrnes, Graham; Brennan, Paul

    2015-01-01

    Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10-10) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors. PMID:25838448

  3. Distinct binding of BRCA2 BRC repeats to RAD51 generates differential DNA damage sensitivity

    PubMed Central

    Chatterjee, Gouri; Jimenez-Sainz, Judit; Presti, Thomas; Nguyen, Tiffany; Jensen, Ryan B.

    2016-01-01

    BRCA2 is a multi-faceted protein critical for the proper regulation of homology-directed repair of DNA double-strand breaks. Elucidating the mechanistic features of BRCA2 is crucial for understanding homologous recombination and how patient-derived mutations impact future cancer risk. Eight centrally located BRC repeats in BRCA2 mediate binding and regulation of RAD51 on resected DNA substrates. Herein, we dissect the biochemical and cellular features of the BRC repeats tethered to the DNA binding domain of BRCA2. To understand how the BRC repeats and isolated domains of BRCA2 contribute to RAD51 binding, we analyzed both the biochemical and cellular properties of these proteins. In contrast to the individual BRC repeat units, we find that the BRC5–8 region potentiates RAD51-mediated DNA strand pairing and provides complementation functions exceeding those of BRC repeats 1–4. Furthermore, BRC5–8 can efficiently repair nuclease-induced DNA double-strand breaks and accelerate the assembly of RAD51 repair complexes upon DNA damage. These findings highlight the importance of the BRC5–8 domain in stabilizing the RAD51 filament and promoting homology-directed repair under conditions of cellular DNA damage. PMID:27084934

  4. Nuclear localization of Rad51B is independent of BRCA2

    SciTech Connect

    Miller, K A; Hinz, J M; Yamada, A; Thompson, L H; Albala, J S

    2005-06-28

    Human Rad51 is critical for the maintenance of genome stability through its role in the repair of DNA double-strand breaks. Rad51B (Rad51L1/hRec2) is one of the five known paralogs of human Rad51 found in a multi-protein complex with three other Rad51 paralogs, Rad51C, Rad51D and Xrcc2. Examination of EGFP-Rad51B fusion protein in HeLa S3 cells and immunofluorescence in several human cell lines confirms the nuclear localization of Rad51B. This is the first report to detail putative interactions of a Rad51 paralog protein with BRCA2. Utilization of a BRCA2 mutant cell line, CAPAN-1 suggests that Rad51B localizes to the nucleus independent of BRCA2. Although both Rad51B and BRCA2 are clearly involved in the homologous recombinational repair pathway, Rad51B and BRCA2 do not appear to associate directly. Furthermore, mutations in the KKLK motif of Rad51B, amino acid residues 4-7, mislocalizes Rad51B to the cytoplasm suggesting that this is the nuclear localization signal for the Rad51B protein. Examination of wild-type EGFP-Rad51B fusion protein in mammalian cells deficient in Rad51C showed that Rad51B localizes to the nucleus independent of Rad51C; further suggesting that Rad51B, like Rad51C, contains its own nuclear localization signal.

  5. Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice

    NASA Technical Reports Server (NTRS)

    Donoho, Greg; Brenneman, Mark A.; Cui, Tracy X.; Donoviel, Dorit; Vogel, Hannes; Goodwin, Edwin H.; Chen, David J.; Hasty, Paul

    2003-01-01

    The Brca2 tumor-suppressor gene contributes to genomic stability, at least in part by a role in homologous recombinational repair. BRCA2 protein is presumed to function in homologous recombination through interactions with RAD51. Both exons 11 and 27 of Brca2 code for domains that interact with RAD51; exon 11 encodes eight BRC motifs, whereas exon 27 encodes a single, distinct interaction domain. Deletion of all RAD51-interacting domains causes embryonic lethality in mice. A less severe phenotype is seen with BRAC2 truncations that preserve some, but not all, of the BRC motifs. These mice can survive beyond weaning, but are runted and infertile, and die very young from cancer. Cells from such mice show hypersensitivity to some genotoxic agents and chromosomal instability. Here, we have analyzed mice and cells with a deletion of only the RAD51-interacting region encoded by exon 27. Mice homozygous for this mutation (called brca2(lex1)) have a shorter life span than that of control littermates, possibly because of early onsets of cancer and sepsis. No other phenotype was observed in these animals; therefore, the brca2(lex1) mutation is less severe than truncations that delete some BRC motifs. However, at the cellular level, the brca2(lex1) mutation causes reduced viability, hypersensitivity to the DNA interstrand crosslinking agent mitomycin C, and gross chromosomal instability, much like more severe truncations. Thus, the extreme carboxy-terminal region encoded by exon 27 is important for BRCA2 function, probably because it is required for a fully functional interaction between BRCA2 and RAD51. Copyright 2003 Wiley-Liss, Inc.

  6. Large genomic deletions inactivate the BRCA2 gene in breast cancer families

    PubMed Central

    Agata, S; Dalla, P; Callegaro, M; Scaini, M; Menin, C; Ghiotto, C; Nicoletto, O; Zavagno, G; Chieco-Bianchi, L; D'Andrea, E; Montagna, M

    2005-01-01

    Background: BRCA1 and BRCA2 are the two major genes responsible for the breast and ovarian cancers that cluster in families with a genetically determined predisposition. However, regardless of the mutation detection method employed, the percentage of families without identifiable alterations of these genes exceeds 50%, even when applying stringent criteria for family selection. A small but significant increase in mutation detection rate has resulted from the discovery of large genomic alterations in BRCA1. A few studies have addressed the question of whether BRCA2 might be inactivated by the same kinds of alteration, but most were either done on a relatively small number of samples or employed cumbersome mutation detection methods of variable sensitivity. Objective: To analyse 121 highly selected families using the recently available BRCA2 multiplex ligation dependent probe amplification (MLPA) technique. Results: Three different large genomic deletions were identified and confirmed by analysis of the mutant transcript and genomic characterisation of the breakpoints. Conclusions: Contrary to initial suggestions, the presence of BRCA2 genomic rearrangements is worth investigating in high risk breast or ovarian cancer families. PMID:16199546

  7. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

    PubMed

    Gaudet, Mia M; Kirchhoff, Tomas; Green, Todd; Vijai, Joseph; Korn, Joshua M; Guiducci, Candace; Segrè, Ayellet V; McGee, Kate; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Gauthier-Villars, Marion; Sobol, Hagay; Longy, Michel; Frenay, Marc; GEMO Study Collaborators; Hogervorst, Frans B L; Rookus, Matti A; Collée, J Margriet; Hoogerbrugge, Nicoline; van Roozendaal, Kees E P; Piedmonte, Marion; Rubinstein, Wendy; Nerenstone, Stacy; Van Le, Linda; Blank, Stephanie V; Caldés, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Arason, Adalgeir; Johannsson, Oskar T; Barkardottir, Rosa B; Devilee, Peter; Olopade, Olofunmilayo I; Neuhausen, Susan L; Wang, Xianshu; Fredericksen, Zachary S; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Viel, Alessandra; Radice, Paolo; Phelan, Catherine M; Narod, Steven; Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda E; Montagna, Marco; D'Andrea, Emma; Friedman, Eitan; Laitman, Yael; Borg, Ake; Beattie, Mary; Ramus, Susan J; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Tim; Spurdle, Amanda B; Chen, Xiaoqing; Holland, Helene; John, Esther M; Hopper, John L; Buys, Saundra S; Daly, Mary B; Southey, Melissa C; Terry, Mary Beth; Tung, Nadine; Overeem Hansen, Thomas V; Nielsen, Finn C; Greene, Mark H; Greene, Mark I; Mai, Phuong L; Osorio, Ana; Durán, Mercedes; Andres, Raquel; Benítez, Javier; Weitzel, Jeffrey N; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Platte, Radka; Evans, D Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Walker, Lisa; Eason, Jacqueline; Barwell, Julian; Godwin, Andrew K; Schmutzler, Rita K; Wappenschmidt, Barbara; Engert, Stefanie; Arnold, Norbert; Gadzicki, Dorothea; Dean, Michael; Gold, Bert; Klein, Robert J; Couch, Fergus J; Chenevix-Trench, Georgia; Easton, Douglas F; Daly, Mark J; Antoniou, Antonis C; Altshuler, David M; Offit, Kenneth

    2010-10-28

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

  8. Suppression of BRCA2 by Mutant Mitochondrial DNA in Prostate Cancer

    DTIC Science & Technology

    2013-05-01

    clones because luciferase uses ATP for its activity, thus it depletes mtDNA-mutated cells of the energy required for anabolic processes and survival. Of...note, mtDNA-mutated cells have reduced ATP levels due to dysfunctional oxidative phosphorylation. 2.c Assess the role of BRCA2 in preventing...orthotopic model), and measure occurrence of micro- and macro-metastasis by imaging (detection of cellular bioluminescence after injecting luciferin). Harvest

  9. Missense Variants of Uncertain Significance (VUS) Altering the Phosphorylation Patterns of BRCA1 and BRCA2

    PubMed Central

    Tram, Eric; Savas, Sevtap; Ozcelik, Hilmi

    2013-01-01

    Mutations in BRCA1 and BRCA2 are responsible for a large proportion of breast-ovarian cancer families. Protein-truncating mutations have been effectively used in the clinical management of familial breast cancer due to their deleterious impact on protein function. However, the majority of missense variants identified throughout the genes continue to pose an obstacle for predictive informative testing due to low frequency and lack of information on how they affect BRCA1/2 function. Phosphorylation of BRCA1 and BRCA2 play an important role in their function as regulators of DNA repair, transcription and cell cycle in response to DNA damage but whether missense variants of uncertain significance (VUS) are able to disrupt this important process is not known. Here we employed a novel approach using NetworKIN which predicts in vivo kinase-substrate relationship, and evolutionary conservation algorithms SIFT, PolyPhen and Align-GVGD. We evaluated whether 191 BRCA1 and 43 BRCA2 VUS from the Breast Cancer Information Core (BIC) database can functionally alter the consensus phosphorylation motifs and abolish kinase recognition and binding to sites known to be phosphorylated in vivo. Our results show that 13.09% (25/191) BRCA1 and 13.95% (6/43) BRCA2 VUS altered the phosphorylation of BRCA1 and BRCA2. We highlight six BRCA1 (K309T, S632N, S1143F, Q1144H, Q1281P, S1542C) and three BRCA2 (S196I, T207A, P3292L) VUS as potentially clinically significant. These occurred rarely (n<2 in BIC), mutated evolutionarily conserved residues and abolished kinase binding to motifs established in the literature involved in DNA repair, cell cycle regulation, transcription or response to DNA damage. Additionally in vivo phosphorylation sites identified via through-put methods are also affected by VUS and are attractive targets for studying their biological and functional significance. We propose that rare VUS affecting phosphorylation may be a novel and important mechanism for which BRCA1 and

  10. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

    PubMed Central

    Vijai, Joseph; Klein, Robert J.; Kirchhoff, Tomas; McGuffog, Lesley; Barrowdale, Daniel; Dunning, Alison M.; Lee, Andrew; Dennis, Joe; Healey, Sue; Dicks, Ed; Soucy, Penny; Sinilnikova, Olga M.; Pankratz, Vernon S.; Wang, Xianshu; Eldridge, Ronald C.; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Peterlongo, Paolo; Schmutzler, Rita K.; Nathanson, Katherine L.; Piedmonte, Marion; Singer, Christian F.; Thomassen, Mads; Hansen, Thomas v. O.; Neuhausen, Susan L.; Blanco, Ignacio; Greene, Mark H.; Garber, Judith; Weitzel, Jeffrey N.; Andrulis, Irene L.; Goldgar, David E.; D'Andrea, Emma; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; van Rensburg, Elizabeth J.; Arason, Adalgeir; Rennert, Gad; van den Ouweland, Ans M. W.; van der Hout, Annemarie H.; Kets, Carolien M.; Aalfs, Cora M.; Wijnen, Juul T.; Ausems, Margreet G. E. M.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Jacobs, Chris; Adlard, Julian; Tischkowitz, Marc; Porteous, Mary E.; Damiola, Francesca; Golmard, Lisa; Barjhoux, Laure; Longy, Michel; Belotti, Muriel; Ferrer, Sandra Fert; Mazoyer, Sylvie; Spurdle, Amanda B.; Manoukian, Siranoush; Barile, Monica; Genuardi, Maurizio; Arnold, Norbert; Meindl, Alfons; Sutter, Christian; Wappenschmidt, Barbara; Domchek, Susan M.; Pfeiler, Georg; Friedman, Eitan; Jensen, Uffe Birk; Robson, Mark; Shah, Sohela; Lazaro, Conxi; Mai, Phuong L.; Benitez, Javier; Southey, Melissa C.; Schmidt, Marjanka K.; Fasching, Peter A.; Peto, Julian; Humphreys, Manjeet K.; Wang, Qin; Michailidou, Kyriaki; Sawyer, Elinor J.; Burwinkel, Barbara; Guénel, Pascal; Bojesen, Stig E.; Milne, Roger L.; Brenner, Hermann; Lochmann, Magdalena; Aittomäki, Kristiina; Dörk, Thilo; Margolin, Sara; Mannermaa, Arto; Lambrechts, Diether; Chang-Claude, Jenny; Radice, Paolo; Giles, Graham G.; Haiman, Christopher A.; Winqvist, Robert; Devillee, Peter; García-Closas, Montserrat; Schoof, Nils; Hooning, Maartje J.; Cox, Angela; Pharoah, Paul D. P.; Jakubowska, Anna; Orr, Nick; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Hall, Per; Couch, Fergus J.; Simard, Jacques; Altshuler, David; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Offit, Kenneth

    2013-01-01

    Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical

  11. A novel CLCN5 mutation in a boy with asymptomatic proteinuria and focal global glomerulosclerosis.

    PubMed

    Valina, Mary Rose; Larsen, Christopher P; Kanosky, Sherry; Suchy, Sharon F; Nield, Linda S; Onder, Ali Mirza

    2013-11-01

    Dent disease is an X-linked proximal tubulopathy that typically presents with hypercalciuria, low-molecular-weight proteinuria and slow progression to endstage renal disease. We report the case of a 5-year-old boy who presented with asymptomatic nephrotic range proteinuria and was later diagnosed with Dent disease. Absence of specific glomerular pathology in the first kidney biopsy led to erroneous treatment for presumably unsampled primary focal segmental glomerulosclerosis. Aggressive angiotensin blockade and immunosuppression resulted in significant side effects with marginal benefit. The continued nonspecific findings after a second kidney biopsy 2 years later led to the suspicion of a congenital tubulopathy. We detected a novel CLCN5 gene mutation, c.1396G > C, that creates a G466R missense change in the ClC-5 protein. Dent disease should be considered in the differential diagnosis of asymptomatic proteinuria for male patients. Profiling proteinuria in these patients by spot urine albumin/creatinine ratio may give the first clue to a tubulopathy. Determining the extent to which the clinical work-up should proceed for females with Dent phenotype or asymptomatic proteinuria remains to be a challenging clinical dilemma.

  12. Characterization of BRCA2 Transcriptional Regulation

    DTIC Science & Technology

    2001-12-01

    effect of the estrogen analogues TCDD and Quercetin on the promoter because the minimal promoter contains two xenobiotic response elements (XRE sites...24hrs these cells were exposed to 2, 5, or 10 nM TCDD, or 5, 10, 25, 50, and 100 iM Quercetin . Neither agent altered promoter activity by greater than 2...analogues quercetin and TCDD have no effect on the BRCA2 promoter Showed that the androgen receptor and the estrogen receptor have no direct effect on the

  13. Effect of the expression of BRCA2 on spontaneous homologous recombination and DNA damage-induced nuclear foci in Saccharomyces cerevisiae.

    PubMed

    Spugnesi, Laura; Balia, Cristina; Collavoli, Anita; Falaschi, Elisabetta; Quercioli, Valentina; Caligo, Maria Adelaide; Galli, Alvaro

    2013-03-01

    The tumour-suppressor gene BRCA2 has been demonstrated to be involved in maintenance of genome integrity by affecting DNA double-strand break repair and homologous recombination. Protein-truncating mutations in BRCA2 predispose women to early onset breast and ovarian cancers and account for 15-30% of familial breast cancer risk. In contrast, the human cancer risk due to missense mutations, intronic variants, and in-frame deletions and insertions in the BRCA2 gene, called unclassified variants, has not been determined. Here, we want to define if the yeast Saccharomyces cerevisiae is a good model to study the role of BRCA2 in DNA recombination and repair and to characterise the unclassified BRCA2 missense variants. Therefore, we expressed the wild-type BRCA2 in yeast and determined the effect of BRCA2 on yeast homologous recombination, methyl methanesulphonate (MMS)-induced Rad51 and Rad52 foci and MMS sensitivity. The expression of BRCA2 induces a high increase in both intra- and inter-recombination events and confers a higher MMS resistance as compared with the negative control. This may suggest that BRCA2 gets involved in DNA repair pathways in yeast. Moreover, the expression of BRCA2 did not affect the number of cells carrying Rad51 or Rad52 nuclear foci. Finally, we aimed to investigate if yeast could be reliable system to set up a functional assay to distinguish a mutated protein from a neutral polymorphism. Therefore, we have expressed two neutral (M1915T and A2951T) and one pathogenic variant (G2748D) in yeast and checked the effect on recombination. The neutral M1915T variant increased intra-chromosomal recombination by almost 2-fold and the other neutral A2975T variant increased intra-chromosomal recombination 2.5-fold as compared with the control. On the other end, the pathogenic variant G2748D did not increase intra- and inter-chromosomal recombination in yeast and, consequently, confers a phenotype very different from the wild-type BRCA2. Moreover, we

  14. Intracellular location of BRCA2 protein expression and prostate cancer progression in the Swedish Watchful Waiting Cohort.

    PubMed

    Thorgeirsson, Tryggvi; Jordahl, Kristina M; Flavin, Richard; Epstein, Mara Meyer; Fiorentino, Michelangelo; Andersson, Swen-Olof; Andren, Ove; Rider, Jennifer R; Mosquera, Juan Miguel; Ingoldsby, Helen; Fall, Katja; Tryggvadottir, Laufey; Mucci, Lorelei A

    2016-03-01

    Prostate cancer patients with inherited BRCA2 mutations have a survival disadvantage. However, it is unknown whether progression is associated with BRCA2 protein expression in diagnostic prostate cancer tissue, among men without inherited mutations. We conducted a nested case-control study within the Swedish Watchful Waiting cohort. The case group included all 71 patients who died from prostate cancer within 5 years from diagnosis and controls were all patients (n = 165) who lived at least 7 years after diagnosis. Tissue microarrays were stained using antibodies for C- and N-terminal domains of the BRCA2 protein. Location (nuclear, cytoplasmic and membranous) and magnitude (intensity and percentage) of expression were assessed. Logistic regression models produced odds ratios (OR) and 95% confidence intervals (CI) adjusted for age, year of diagnosis and Gleason score. Positive BRCA2 staining at the cell membrane was associated with reduced risk of death within 5 years (N-terminal: OR = 0.47, 95% CI = 0.21-1.04, P = 0.06; C-terminal: OR = 0.41, 95% CI = 0.18-0.91, P = 0.03) and low Gleason scores (P = 0.006). Positive cytoplasmic C-terminal staining was associated with higher Gleason scores and increased lethality (OR = 3.61, 95% CI = 1.61-8.07, P = 0.002). BRCA2 protein expression at the cell membrane and lack of C-terminal expression in the cytoplasm were associated with a reduced risk of rapidly fatal prostate cancer. BRCA2 protein expression in prostate cancer tissue may have independent prognostic value. The potential biological significance of BRCA2 expression at the cell membrane warrants further investigation.

  15. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary

    PubMed Central

    van Asperen, C J; Brohet, R; Meijers-Heijboer, E; Hoogerbrugge, N; Verhoef, S; Vasen, H; Ausems, M; Menko, F; Gomez, G; Klijn, J; Hogervorst, F; van Houwelingen, J C; van't, V; Rookus, M; van Leeuwen, F E; on, b

    2005-01-01

    Background: In BRCA2 mutation carriers, increased risks have been reported for several cancer sites besides breast and ovary. As most of the families included in earlier reports were selected on the basis of multiple breast/ovarian cancer cases, it is possible that risk estimates may differ in mutation carriers with a less striking family history. Methods: In the Netherlands, 139 BRCA2 families with 66 different pathogenic mutations were included in a nationwide study. To avoid testing bias, we chose not to estimate risk in typed carriers, but rather in male and female family members with a 50% prior probability of being a carrier (n = 1811). The relative risk (RR) for each cancer site with the exception of breast and ovarian cancer was determined by comparing observed numbers with those expected, based on Dutch cancer incidence rates. Results: We observed an excess risk for four cancer sites: pancreas (RR 5.9; 95% confidence interval (CI) 3.2 to 10.0), prostate (2.5; 1.6 to 3.8), bone (14.4; 2.9 to 42.1) and pharynx (7.3; 2.0 to 18.6). A small increase was observed for cancer of the digestive tract (1.5; 1.1 to 1.9). Histological verification was available for 46% of the tumours. Nearly all increased risks reached statistical significance for men only. Cancer risks tended to be higher for people before the age of 65 years. Moreover, families with mutations outside the previously defined ovarian cancer cluster region tended to have a higher cancer risk. Conclusions: We found that BRCA2 carriers are at increased risk for cancers of the prostate and pancreas, and possibly bone and pharynx. Larger databases with extended follow up are needed to provide insight into mutation specific risks of selected carriers in BRCA2 families. PMID:16141007

  16. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women

    SciTech Connect

    Abeliovich, D.; Lerer, I.; Weinberg, N.

    1997-03-01

    The mutations 185delAG, 188del11, and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene were analyzed in 199 Ashkenazi and 44 non-Ashkenazi Jewish unrelated patients with breast and/or ovarian cancer. Of the Jewish Ashkenazi women with ovarian cancer, 62% (13/21) had one of the target mutations, as did 30% (13/43) of women with breast cancer alone diagnosed before the age 40 years and 10% (15/141) of those with breast cancer diagnosed after the age 40 years. Age at ovarian cancer diagnosis was not associated with carrier status. Of 99 Ashkenazi patients with no family history of breast and/or ovarian cancer, 10% carried one of the mutations; in two of them the mutation was proved to be paternally transmitted. One non-Ashkenazi Jewish ovarian cancer patient from Iraq carried the 185delAG mutation. Individual mutation frequencies among breast cancer Ashkenazi patients were 6.7% for 185delAG, 2.2% for 5382insC, and 4.5% for 6174delT, among ovarian cancer patients; 185delAG and 6174delT were about equally common (33% and 29%, respectively), but no ovarian cancer patient carried the 5382insC. More mutations responsible for inherited breast and ovarian cancer probably remain to be found in this population, since 79% of high-incidence breast cancer families and 35% of high-incidence breast/ovarian cancer families had none of the three known founder mutations. 25 refs., 3 figs., 6 tabs.

  17. Modifiers of the Efficacy of Risk-Reducing Salpingo-Oophorectomy for the Prevention of Breast and Ovarian Cancer in Carriers of BRCA1 and BRCA2

    DTIC Science & Technology

    2006-05-01

    mutations in formalin-fixed paraffin-embedded tissue; 4) Continuation of formal training in genetic epidemiology laboratory methods, outcomes analysis ...structural analysis of BRCA2 variants of uncertain significance. 15. SUBJECT TERMS BRCA1, BRCA2, Breast Cancer, Ovarian Cancer, Prophylactic...analyzed for each of the specific aims using Kaplan-Meier analysis and a Cox proportion hazards model. Total planned accrual through April 30, 2007 is

  18. Analysis of BRCA1and BRCA2 large genomic rearrangements in Sri Lankan familial breast cancer patients and at risk individuals

    PubMed Central

    2014-01-01

    Background Majority of mutations found to date in the BRCA1/BRCA2 genes in breast and/or ovarian cancer families are point mutations or small insertions and deletions scattered over the coding sequence and splice junctions. Such mutations and sequence variants of BRCA1 and BRCA2 genes were previously identified in a group of Sri Lankan breast cancer patients. Large genomic rearrangements have been characterized in BRCA1 and BRCA2 genes in several populations but these have not been characterized in Sri Lankan breast cancer patients. Findings A cohort of familial breast cancer patients (N = 57), at risk individuals (N = 25) and healthy controls (N = 23) were analyzed using multiplex ligation-dependent probe amplification method to detect BRCA1 and BRCA2 large genomic rearrangements. One familial breast cancer patient showed an ambiguous deletion in exon 6 of BRCA1 gene. Full sequencing of the ambiguous region was used to confirm MLPA results. Ambiguous deletion detected by MLPA was found to be a false positive result confirming that BRCA1 large genomic rearrangements were absent in the subjects studied. No BRCA2 rearrangement was also identified in the cohort. Conclusion Thus this study demonstrates that BRCA1 and BRCA2 large genomic rearrangements are unlikely to make a significant contribution to aetiology of breast cancer in Sri Lanka. PMID:24906410

  19. Twenty-three novel BRCA1 and BRCA2 sequence alterations in breast and/or ovarian cancer families of Eastern Spain.

    PubMed

    Esteban Cardeñosa, Eva; Bolufer Gilabert, Pascual; Palanca Suela, Sarai; Oltra Soler, Silvestre; Barragán González, Eva; Velasco Sampedro, Eladio; Chirivella González, Isabel; Segura Huerta, Angel; Guillén Ponce, Carmen; Martínez de Dueñas, Eduardo

    2008-11-01

    It is well established that mutations in BRCA1 and BRCA2 genes significantly increase the risk of breast and ovarian cancer. We here report 23 novel genetic variants of the BRCA1 and BRCA2 genes found in 349 cancer-prone unrelated families from Eastern Spain detected during the first 2 years of performance of the Program of Genetic Counseling of Valencia Community. Mutational screening was performed by pre-screening the heteroduplex formed in the PCR products obtained amplifying BRCA1 and BRCA2 genes by conformation sensitive electrophoresis. We detected 10 deletereous mutations, four in BRCA1 (three frame-shift (FS) and one nonsense mutation (NS)) and six in BRCA2 (four FS and one NS mutation). Moreover, we detected 13 unclassified variants, four in BRCA1 (one missense (MS), two synonymous (SYN) and one intronic (I) variant) and nine in BRCA2 (six MS, one SYN and two I). The relevance of the novel mutations is discussed. Our contribution broadens the BRCA1/2 world mutational spectra.

  20. Post-transcriptional Regulation of BRCA2 through Interactions with miR-19a and miR-19b

    PubMed Central

    Mogilyansky, Elena; Clark, Peter; Quann, Kevin; Zhou, Honglei; Londin, Eric; Jing, Yi; Rigoutsos, Isidore

    2016-01-01

    Breast cancer type 2, early onset susceptibility gene (BRCA2) is a major component of the homologous recombination DNA repair pathway. It acts as a tumor suppressor whose function is often lost in cancers. Patients with specific mutations in the BRCA2 gene often display discrete clinical, histopathological, and molecular features. However, a subset of sporadic cancers has wild type BRCA2 and display defects in the homology-directed repair pathway, which is the hallmark of ‘BRCAness.’ The mechanisms by which BRCAness arises are not well understood but post-transcriptional regulation of BRCA2 gene expression by microRNAs (miRNAs) may contribute to this phenotype. Here, we examine the post-transcriptional effects that some members of the six-miRNA cluster known as the miR-17/92 cluster have on the abundance of BRCA2’s messenger RNA (mRNA) and protein. We discuss two interactions involving the miR-19a and miR-19b members of the cluster and the 3′UTR of BRCA2’s mRNA. We investigated these miRNA:mRNA interactions in 15 cell lines derived from pancreatic, breast, colon, and kidney tissue. We show that over-expression of these two miRNAs results in a concomitant decrease of BRCA2’s mRNA and protein expression in a subset of the tested cell lines. Additionally, using luciferase reporter assays we identified direct interactions between miR-19a/miR-19b and a miRNA response element (MRE) in BRCA2’s 3′UTR. Our results suggest that BRCA2 is subject to a complex post-transcriptional regulatory program that has specific dependencies on the genetic and phenotypic background of cell types. PMID:27630665

  1. [BRCA1 and BRCA2 - pathologists starting kit].

    PubMed

    Škapa, Petr

    2016-01-01

    Dysfunction of tumor suppressor genes BRCA1 and BRCA2 is involved in the pathogenesis of malignant tumors, especially breast and ovarian carcinoma. BRCA1/2 genes may be inactivated by germinal and somatic mutations or epigenetic changes. Germinal mutations are responsible for the hereditary breast and ovarian carcinoma syndrome. Defects of BRCA1/2 genes lead to the failure of homologous recombination, the basic mechanism for DNA double strand break repair. The resultant genomic instability is associated with a high risk of malignant transformation of the cell, but it also results in a higher sensitivity of tumors to platinum-based chemotherapeutic compounds which damage DNA structure directly. Inhibitors of poly(ADP-ribose) polymerase (PARP) are the next generation of antitumor agents aimed on the suppression of DNA single strand break repair. In homologous recombination deficient tumors, PARP inhibitors lead to accumulation of DNA damage and death of neoplastic cells through the mechanism of synthetic lethality. Platinum-based agents and PARP inhibitors are effective not only against tumors with germinal and somatic BRCA1/2 mutations but also against sporadic carcinomas with epigenetic BRCA1/2 inactivation or with defects of other independent genes involved in the control of homologous recombination. This phenomenon is represented by the term "BRCAness". Mutational analysis is used for the assessment of BRCA1/2 status, but it is complicated by the prominent length of BRCA1/2 genes and a wide spectrum of possible genetic alterations. Therefore, next generation sequencing seems to represent an optimal approach for BRCA1/2 evaluation nowadays. Development of reliable diagnostic tests for BRCAness in sporadic tumors and efforts to reverse platinum and PARP inhibitors resistance represent the key objectives of the forthcoming research.

  2. Functional assays for analysis of variants of uncertain significance in BRCA2

    PubMed Central

    Guidugli, Lucia; Carreira, Aura; Caputo, Sandrine M.; Ehlen, Asa; Galli, Alvaro; Monteiro, Alvaro N.A.; Neuhausen, Susan L.; Hansen, Thomas V.O.; Couch, Fergus J.; Vreeswijk, Maaike P.G.

    2014-01-01

    Missense variants in the BRCA2 gene are routinely detected during clinical screening for pathogenic mutations in patients with a family history of breast and ovarian cancer. These subtle changes frequently remain of unknown clinical significance because of the lack of genetic information that may help establish a direct correlation with cancer predisposition. Therefore alternative ways of predicting the pathogenicity of these variants are urgently needed. Since BRCA2 is a protein involved in important cellular mechanisms such as DNA repair, replication and cell cycle control, functional assays have been developed that exploit these cellular activities to explore the impact of the variants on protein function. In this review we summarize assays developed and currently utilized for studying missense variants in BRCA2. We specifically depict details of each assay, including VUS analyzed, and describe a validation set of (genetically) proven pathogenic and neutral missense variants to serve as a golden standard for the validation of each assay. Guidelines are proposed to enable implementation of laboratory-based methods to assess the impact of the variant on cancer risk. PMID:24323938

  3. Diagnostic and therapeutic ionizing radiation and the risk of a first and second primary breast cancer, with special attention for BRCA1 and BRCA2 mutation carriers: a critical review of the literature.

    PubMed

    Drooger, Jan C; Hooning, Maartje J; Seynaeve, Caroline M; Baaijens, Margreet H A; Obdeijn, Inge Marie; Sleijfer, Stefan; Jager, Agnes

    2015-02-01

    Occurrence of breast cancer is a well-known long-term side effect of ionizing radiation (both diagnostic and therapeutic). The radiation-induced breast cancer risk increases with longer follow-up, higher radiation dose and younger age of exposure. The risk for breast cancer following irradiation for lymphomas is well known. Although data regarding the carcinogenic risk of adjuvant radiotherapy for a primary breast cancer are sparse, an increased risk is suggested with longer follow-up mainly when exposed at younger age. Particularly, patients with a BRCA1/2 mutation might be more sensitive for the deleterious effects of ionizing radiation due to an impaired capacity of repairing double strand DNA breaks. This might have consequences for the use of mammography in breast cancer screening, as well as the choice between breast conserving therapy including radiotherapy and mastectomy at primary breast cancer diagnosis in young BRCA1/2 mutation carriers. Good data regarding this topic, however, are scarce, mainly due to constraints in the design of performed studies. In this review, we will discuss the current literature on the association between ionizing radiation and developing breast cancer, with particular attention to patients with a BRCA1/2 mutation.

  4. "The bigger the network the bigger the bowl of cherries...": exploring the acceptability of, and preferences for, an ongoing support network for known BRCA 1 and BRCA 2 mutation carriers.

    PubMed

    Hughes, Lisa; Phelps, Ceri

    2010-10-01

    There is increasing evidence to suggest that the ongoing information and support needs of BRCA gene mutation carriers are not being met. This qualitative study investigated preferences for an on-going support network for mutation carriers in Wales, UK. Seventeen female BRCA1/2 mutation carriers participated in focus groups which explored their current and on-going information and psychological support needs. The interviews were transcribed and thematically analysed. The results reflected a diversity of experiences and support needs. The majority of participants felt they and their families would benefit from an on-going 'support network' which should incorporate information-provision alongside elements of a traditional support group alongside, internet-based support such as web-based chat forums, matching schemes and professionally led workshops. Some degree of professional input into any such initiative was believed to be important. This study has informed the development of an appropriate support network based on a hub and spoke model to help carriers and their families adapt to living and coping with their genetic risk.

  5. Detection of genomic variations in BRCA1 and BRCA2 genes by long-range PCR and next-generation sequencing.

    PubMed

    Hernan, Imma; Borràs, Emma; de Sousa Dias, Miguel; Gamundi, María José; Mañé, Begoña; Llort, Gemma; Agúndez, José A G; Blanca, Miguel; Carballo, Miguel

    2012-01-01

    Advances in sequencing technologies, such as next-generation sequencing (NGS), represent an opportunity to perform genetic testing in a clinical scenario. In this study, we developed and tested a method for the detection of mutations in the large BRCA1 and BRCA2 tumor suppressor genes, using long-range PCR (LR-PCR) and NGS, in samples from individuals with a personal and/or family history of breast and/or ovarian cancer. Eleven LR-PCR fragments, between 3000 and 15,300 bp, containing all coding exons and flanking splice junctions of BRCA1 and BRCA2, were obtained from DNA samples of five individuals carrying mutations in either BRCA1 or BRCA2. Libraries for NGS were prepared using an enzymatic (Nextera technology) method. We analyzed five individual samples in parallel by NGS and obtained complete coverage of all LR-PCR fragments, with an average coding sequence depth for each nucleotide of >30 reads, running from ×7 (in exon 22 of BRCA1) to >×150. We detected and confirmed 100% of the mutations that predispose to the risk of cancer, together with other genomic variations in BRCA1 and BRCA2. Our approach demonstrates that genomic LR-PCR, together with NGS, using the GS Junior 454 System platform, is an effective method for patient sample analysis of BRCA1 and BRCA2 genes. In addition, this method could be performed in regular molecular genetics laboratories.

  6. Familial Creutzfeldt-Jakob disease with the E200K mutation: longitudinal neuroimaging from asymptomatic to symptomatic CJD.

    PubMed

    Cohen, Oren S; Chapman, Joab; Korczyn, Amos D; Nitsan, Zeev; Appel, Shmuel; Hoffmann, Chen; Rosenmann, Hanna; Kahana, Esther; Lee, Hedok

    2015-03-01

    Familial Creutzfeldt-Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the PRNP gene. While carriers are born with this mutation, they usually remain asymptomatic until middle age. Early detection of conversion is crucial for understanding and eventually for the treatment of the disease. The aim of this study was to report longitudinal MRI data in E200K individuals who eventually converted from healthy mutation carriers to clinically symptomatic CJD. As a part of a prospective study, asymptomatic E200K mutation carriers were scanned annually until their conversion to symptomatic disease. Standardized diffusion and anatomical MR sequences were performed before and after clinical conversion in the subjects and those were compared to 15 non-carrier siblings ("healthy controls"). Blinded radiological readings and region of interest analyses were performed. Radiological readings of individual cases failed to detect characteristic changes in the scans taken before the conversion. Region of interest analysis of diffusion changes in pre-symptomatic stage was inconclusive; however, ADC reduction was found in early and late stages of the disease. Computerized volumetric analysis revealed monotonic volume reductions in thalamus, putamen and caudate following conversion, and the lateral ventricles showed dilatation of up to 62 % after clinical conversion. Although the clinical manifestations at disease onset are variable, the diffusion abnormalities and/or volume changes in the thalamus and basal ganglia during conversion may indicate early involvement of the thalamostriatal neuronal circuit.

  7. Functional Study of the Human BRCA2 Tumor Suppressor

    DTIC Science & Technology

    2005-08-01

    P/CAF21, 21, DSS129 , BRAF35 30, androgen receptor (AR)21, Polo-like kinase Plk131, FANCD2 /G3 2’ ", BCCIPa/p334 and the recently identified potential...monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol 24, 5850-62 (2004). 18. Lomonosov, M., Anand, S., Sangrithi, M., Davies, R. & Venkitaraman, A...33. Hussain, S. et al. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hum Mol Genet 13, 1241-8 (2004). 34. Lu, H. et al

  8. An integrated in silico approach to analyze the involvement of single amino acid polymorphisms in FANCD1/BRCA2-PALB2 and FANCD1/BRCA2-RAD51 complex.

    PubMed

    Doss, C George Priya; Nagasundaram, N

    2014-11-01

    Fanconi anemia (FA) is an autosomal recessive human disease characterized by genomic instability and a marked increase in cancer risk. The importance of FANCD1 gene is manifested by the fact that deleterious amino acid substitutions were found to confer susceptibility to hereditary breast and ovarian cancers. Attaining experimental knowledge about the possible disease-associated substitutions is laborious and time consuming. The recent introduction of genome variation analyzing in silico tools have the capability to identify the deleterious variants in an efficient manner. In this study, we conducted in silico variation analysis of deleterious non-synonymous SNPs at both functional and structural level in the breast cancer and FA susceptibility gene BRCA2/FANCD1. To identify and characterize deleterious mutations in this study, five in silico tools based on two different prediction methods namely pathogenicity prediction (SIFT, PolyPhen, and PANTHER), and protein stability prediction (I-Mutant 2.0 and MuStab) were analyzed. Based on the deleterious scores that overlap in these in silico approaches, and the availability of three-dimensional structures, structure analysis was carried out with the major mutations that occurred in the native protein coded by FANCD1/BRCA2 gene. In this work, we report the results of the first molecular dynamics (MD) simulation study performed to analyze the structural level changes in time scale level with respect to the native and mutated protein complexes (G25R, W31C, W31R in FANCD1/BRCA2-PALB2, and F1524V, V1532F in FANCD1/BRCA2-RAD51). Analysis of the MD trajectories indicated that predicted deleterious variants alter the structural behavior of BRCA2-PALB2 and BRCA2-RAD51 protein complexes. In addition, statistical analysis was employed to test the significance of these in silico tool predictions. Based on these predictions, we conclude that the identification of disease-related SNPs by in silico methods, in combination with MD

  9. Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors

    PubMed Central

    Huang, Fei; Goyal, Nadish; Sullivan, Katherine; Hanamshet, Kritika; Patel, Mikir; Mazina, Olga M.; Wang, Charles X.; An, W. Frank; Spoonamore, James; Metkar, Shailesh; Emmitte, Kyle A.; Cocklin, Simon; Skorski, Tomasz; Mazin, Alexander V.

    2016-01-01

    RAD52 is a member of the homologous recombination (HR) pathway that is important for maintenance of genome integrity. While single RAD52 mutations show no significant phenotype in mammals, their combination with mutations in genes that cause hereditary breast cancer and ovarian cancer like BRCA1, BRCA2, PALB2 and RAD51C are lethal. Consequently, RAD52 may represent an important target for cancer therapy. In vitro, RAD52 has ssDNA annealing and DNA strand exchange activities. Here, to identify small molecule inhibitors of RAD52 we screened a 372,903-compound library using a fluorescence-quenching assay for ssDNA annealing activity of RAD52. The obtained 70 putative inhibitors were further characterized using biochemical and cell-based assays. As a result, we identified compounds that specifically inhibit the biochemical activities of RAD52, suppress growth of BRCA1- and BRCA2-deficient cells and inhibit RAD52-dependent single-strand annealing (SSA) in human cells. We will use these compounds for development of novel cancer therapy and as a probe to study mechanisms of DNA repair. PMID:26873923

  10. Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions.

    PubMed

    Zámborszky, J; Szikriszt, B; Gervai, J Z; Pipek, O; Póti, Á; Krzystanek, M; Ribli, D; Szalai-Gindl, J M; Csabai, I; Szallasi, Z; Swanton, C; Richardson, A L; Szüts, D

    2017-02-09

    Loss-of-function mutations in the BRCA1 and BRCA2 genes increase the risk of cancer. Owing to their function in homologous recombination repair, much research has focused on the unstable genomic phenotype of BRCA1/2 mutant cells manifest mainly as large-scale rearrangements. We used whole-genome sequencing of multiple isogenic chicken DT40 cell clones to precisely determine the consequences of BRCA1/2 loss on all types of genomic mutagenesis. Spontaneous base substitution mutation rates increased sevenfold upon the disruption of either BRCA1 or BRCA2, and the arising mutation spectra showed strong and specific correlation with a mutation signature associated with BRCA1/2 mutant tumours. To model endogenous alkylating damage, we determined the mutation spectrum caused by methyl methanesulfonate (MMS), and showed that MMS also induces more base substitution mutations in BRCA1/2-deficient cells. Spontaneously arising and MMS-induced insertion/deletion mutations and large rearrangements were also more common in BRCA1/2 mutant cells compared with the wild-type control. A difference in the short deletion phenotypes of BRCA1 and BRCA2 suggested distinct roles for the two proteins in the processing of DNA lesions, as BRCA2 mutants contained more short deletions, with a wider size distribution, which frequently showed microhomology near the breakpoints resembling repair by non-homologous end joining. An increased and prolonged gamma-H2AX signal in MMS-treated BRCA1/2 cells suggested an aberrant processing of stalled replication forks as the cause of increased mutagenesis. The high rate of base substitution mutagenesis demonstrated by our experiments is likely to significantly contribute to the oncogenic effect of the inactivation of BRCA1 or BRCA2.

  11. Asymptomatic Congenital Hyperinsulinism due to a Glucokinase-Activating Mutation, Treated as Adrenal Insufficiency for Twelve Years

    PubMed Central

    Morishita, Kae; Kyo, Chika; Kosugi, Rieko; Ogawa, Tatsuo; Inoue, Tatsuhide

    2017-01-01

    Congenital hyperinsulinism (CHI) caused by a glucokinase- (GCK-) activating mutation shows autosomal dominant inheritance, and its severity ranges from mild to severe. A 43-year-old female with asymptomatic hypoglycemia (47 mg/dL) was diagnosed as partial adrenal insufficiency and the administration of hydrocortisone (10 mg/day) was initiated. Twelve years later, her 8-month-old grandchild was diagnosed with CHI. Heterozygosity of exon 6 c.590T>C (p.M197T) was identified in a gene analysis of GCK, which was also detected in her son and herself. The identification of GCK-activating mutations in hyperinsulinemic hypoglycemia patients may be useful for a deeper understanding of the pathophysiology involved and preventing unnecessary glucocorticoid therapy. PMID:28163940

  12. Long Term Outcomes of BRCA1/BRCA2 Mutation Testing

    DTIC Science & Technology

    2007-08-01

    associated with disclosure. Table 2. Association of closeness with disclosure Relatives rpb sry (1.2) Mothers Fathers Sisters Brothers Spouses...correlation between closeness and disclosure; sry (1.2) denotes semi-partial correlation between closeness and disclosure, controlling for test results

  13. Long Term Outcomes of BRCA1/BRCA2 Mutation Testing

    DTIC Science & Technology

    2008-08-01

    Table 2. Association of closeness with disclosure Relatives rpb sry (1.2) Mothers Fathers Sisters Brothers Spouses Children > 18 Children...closeness and disclosure; sry (1.2) denotes semi-partial correlation between closeness and disclosure, controlling for test results. 8 Regardless of RRO

  14. Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas

    PubMed Central

    Weren, Robbert D.A.; Mensenkamp, Arjen R.; Simons, Michiel; Eijkelenboom, Astrid; Sie, Aisha S.; Ouchene, Hicham; van Asseldonk, Monique; Gomez‐Garcia, Encarna B.; Blok, Marinus J.; de Hullu, Joanne A.; Nelen, Marcel R.; Hoischen, Alexander; Bulten, Johan; Tops, Bastiaan B.J.; Hoogerbrugge, Nicoline

    2016-01-01

    ABSTRACT With the recent introduction of Poly(ADP‐ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin‐fixed, paraffin‐embedded (FFPE) tissue, we have developed a single‐molecule molecular inversion probe (smMIP)‐based targeted next‐generation sequencing (NGS) approach. Our smMIP‐based NGS approach provides analysis of both strands of the open reading frame of BRCA1 and BRCA2, enabling the discrimination between real variants and formalin‐induced artefacts. The single molecule tag enables compilation of unique reads leading to a high analytical sensitivity and enabling assessment of the reliability of mutation‐negative results. Multiplex ligation‐dependent probe amplification (MLPA) and Methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) were used to detect exon deletions of BRCA1 and methylation of the BRCA1 promoter, respectively. Here, we show that this combined approach allows the rapid and reliable detection of both germline and somatic aberrations affecting BRCA1 and BRCA2 in DNA derived from FFPE OCs, enabling improved hereditary cancer risk assessment and clinical treatment of ovarian cancer patients. PMID:27767231

  15. A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects

    PubMed Central

    Jervis, Sarah; Song, Honglin; Lee, Andrew; Dicks, Ed; Harrington, Patricia; Baynes, Caroline; Manchanda, Ranjit; Easton, Douglas F; Jacobs, Ian; Pharoah, Paul P D; Antoniou, Antonis C

    2015-01-01

    Background Although BRCA1 and BRCA2 mutations account for only ∼27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1, BRCA2 and other familial factors. Therefore, a currently unresolved problem in clinical genetics is how to counsel women with family history of OvC but no identifiable BRCA1/2 mutations. Methods We used data from 1548 patients with OvC and their relatives from a population-based study, with known BRCA1/2 mutation status, to investigate OvC genetic susceptibility models, using segregation analysis methods. Results The most parsimonious model included the effects of BRCA1/2 mutations, and the residual familial aggregation was accounted for by a polygenic component (SD 1.43, 95% CI 1.10 to 1.86), reflecting the multiplicative effects of a large number of genes with small contributions to the familial risk. We estimated that 1 in 630 individuals carries a BRCA1 mutation and 1 in 195 carries a BRCA2 mutation. We extended this model to incorporate the explicit effects of 17 common alleles that are associated with OvC risk. Based on our models, assuming all of the susceptibility genes could be identified we estimate that the half of the female population at highest genetic risk will account for 92% of all OvCs. Conclusions The resulting model can be used to obtain the risk of developing OvC on the basis of BRCA1/2, explicit family history and common alleles. This is the first model that accounts for all OvC familial aggregation and would be useful in the OvC genetic counselling process. PMID:26025000

  16. The Functions of BRCA2 in Homologous Recombinational Repair

    DTIC Science & Technology

    2006-07-01

    frequency Results on protein purification: We have expressed the human Rad51 protein in insect cells Sf9 using the baculovirus system. The Rad51 protein...fragments of BRCA2 in Sf9 cells. The BRC1-4, BRC5-8, and BRC1-8 domains encode the proteins of 80-kDa, 65- kDa, and 138-kDa, respectively. The

  17. Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice-site prediction programs.

    PubMed

    Vreeswijk, Maaike P G; Kraan, Jaennelle N; van der Klift, Heleen M; Vink, Geraldine R; Cornelisse, Cees J; Wijnen, Juul T; Bakker, Egbert; van Asperen, Christi J; Devilee, Peter

    2009-01-01

    A large number of sequence variants identified in BRCA1 and BRCA2 cannot be distinguished as either disease-causing mutations or neutral variants. These so-called unclassified variants (UVs) include variants that are located in the intronic sequences of BRCA1 and BRCA2. The purpose of this study was to assess the use of splice-site prediction programs (SSPPs) to select intronic variants in BRCA1 and BRCA2 that are likely to affect RNA splicing. We performed in vitro molecular characterization of RNA of six intronic variants in BRCA1 and BRCA2. In four cases (BRCA1, c.81-6T>A and c.4986+5G>T; BRCA2, c.7617+2T>G and c.8754+5G>A) a deleterious effect on RNA splicing was seen, whereas the c.135-15_-12del variant in BRCA1 showed no effect on RNA splicing. In the case of the BRCA2 c.68-7T>A variant, RNA analysis was not sufficient to establish the clinical significance. Six SSPPs were used to predict whether an effect on RNA splicing was expected for these six variants as well as for 23 intronic variants in BRCA1 for which the effect on RNA splicing has been published. Out of a total of 174 predictions, 161 (93%) were informative (i.e., the wild-type splice-site was recognized). No false-negative predictions were observed; an effect on RNA splicing was always predicted by these programs. In four cases (2.5%) a false-positive prediction was observed. For DNA diagnostic laboratories, these programs are therefore very useful to select intronic variants that are likely to affect RNA splicing for further analysis.

  18. Somatic SNPs of the BRCA2 gene at the fragments encoding RAD51 binding sites of canine mammary tumors.

    PubMed

    Ozmen, O; Kul, S; Risvanli, A; Ozalp, G; Sabuncu, A; Kul, O

    2017-01-30

    Mammary tumors are the most common tumor type both in women and in female dogs. In women, heritable breast cancers have been linked mutations in the breast cancer susceptibility gene BRCA2 and it contains eight BRC repeats in exon 11 that bind to RAD51. In this study, we investigated the sequence variations of BRC1-BRC8 and C-terminus of canine BRCA2 gene. From a total of 64 canine patients with mammary tumors, 31 mammary tumors with benign and malign carcinomas and the 3 normal mammary glands were used for the study. In this study, 19 SNPs of exon 11 of BRCA2 in canine mammary tumors were detected for the first time. The c.2383A>C (T1425P) SNP was found to be the most probable disease-associated nsSNP. Our findings suggest that T1425P variation in BRC3 to be the most probable disease-associated nsSNP and may affect RAD51 binding strength.

  19. Attitudes, knowledge, risk perceptions and decision-making among women with breast and/or ovarian cancer considering testing for BRCA1 and BRCA2 and their spouses.

    PubMed

    Bluman, Leslie G; Rimer, Barbara K; Regan Sterba, Katherine; Lancaster, Julia; Clark, Shelly; Borstelmann, Nancy; Iglehart, J Dirk; Winer, Eric P

    2003-01-01

    A limited number of studies have examined the involvement of spouses in the decision-making process for genetic testing as well as impact of the actual testing. This report presents data from 40 women with a personal history of breast and/or ovarian cancer who were considering genetic testing for BRCA1 and BRCA2 and their spouses. We examined knowledge and attitudes regarding genetic testing for breast cancer susceptibility, perceptions of the likelihood that their wives (the women) had a BRCA1 or BRCA2 mutation, pros and cons of genetic testing, spouses' satisfaction with their involvement in the decision-making process and additional resources they would find helpful. Knowledge about cancer genetics and genetic testing for BRCA1 and BCA2 was limited among both women and their spouses. Up to one-third of spouses indicated that they would like to avail themselves of additional sources of information about BRCA1 and BRCA2 testing. Most spouses indicated that they thought their wives had a mutation in BRCA1 or BRCA2 and that their wives' breast cancers would recur. Pros of genetic testing were emphasized more than cons among both parties. Overall, spouses were satisfied with their role in the decision-making process. Future interventions to improve the decision-making process regarding genetic testing for breast cancer susceptibility should be undertaken.

  20. Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.

    PubMed

    Pruss, Dmitry; Morris, Brian; Hughes, Elisha; Eggington, Julie M; Esterling, Lisa; Robinson, Brandon S; van Kan, Aric; Fernandes, Priscilla H; Roa, Benjamin B; Gutin, Alexander; Wenstrup, Richard J; Bowles, Karla R

    2014-08-01

    BRCA1 and BRCA2 sequencing analysis detects variants of uncertain clinical significance in approximately 2 % of patients undergoing clinical diagnostic testing in our laboratory. The reclassification of these variants into either a pathogenic or benign clinical interpretation is critical for improved patient management. We developed a statistical variant reclassification tool based on the premise that probands with disease-causing mutations are expected to have more severe personal and family histories than those having benign variants. The algorithm was validated using simulated variants based on approximately 145,000 probands, as well as 286 BRCA1 and 303 BRCA2 true variants. Positive and negative predictive values of ≥99 % were obtained for each gene. Although the history weighting algorithm was not designed to detect alleles of lower penetrance, analysis of the hypomorphic mutations c.5096G>A (p.Arg1699Gln; BRCA1) and c.7878G>C (p.Trp2626Cys; BRCA2) indicated that the history weighting algorithm is able to identify some lower penetrance alleles. The history weighting algorithm is a powerful tool that accurately assigns actionable clinical classifications to variants of uncertain clinical significance. While being developed for reclassification of BRCA1 and BRCA2 variants, the history weighting algorithm is expected to be applicable to other cancer- and non-cancer-related genes.

  1. Predicting the Pathogenic Potential of BRCA1 and BRCA2 Gene Variants Identified in Clinical Genetic Testing

    PubMed Central

    Brookes, Clare; Lai, Stella; Doherty, Elaine; Love, Donald R.

    2015-01-01

    Objectives: Missense variants are very commonly detected when screening for mutations in the BRCA1 and BRCA2 genes. Pathogenic mutations in the BRCA1 and BRCA2 genes lead to an increased risk of developing breast, ovarian, prostate and/or pancreatic cancer. This study aimed to assess the predictive capability of in silico programmes and mutation databases in assisting diagnostic laboratories to determine the pathogenicity of sequence-detectable mutations. Methods: Between July 2011 and April 2013, an analysis was undertaken of 13 missense BRCA gene variants that had been detected in patients referred to the Genetic Health Services New Zealand (Northern Hub) for BRCA gene analysis. The analysis involved the use of 13 in silico protein prediction programmes, two in silico transcript analysis programmes and the examination of three BRCA gene databases. Results: In most of the variants, the analysis showed different in silico interpretations. This illustrates the interpretation challenges faced by diagnostic laboratories. Conclusion: Unfortunately, when using online mutation databases and carrying out in silico analyses, there is significant discordance in the classification of some missense variants in the BRCA genes. This discordance leads to complexities in interpreting and reporting these variants in a clinical context. The authors have developed a simple procedure for analysing variants; however, those of unknown significance largely remain unknown. As a consequence, the clinical value of some reports may be negligible. PMID:26052455

  2. Asymptomatic dystrophinopathy

    SciTech Connect

    Morrone, A. |; Hoffman, E.P.; Hoop, R.C.

    1997-03-31

    A 4-year-old girl was referred for evaluation for a mild but persistent serum aspartate aminotransferase (AST) elevation detected incidentally during routine blood screening for a skin infection. Serum creatine kinase activity was found to be increased. Immuno-histochemical study for dystrophin in her muscle biopsy showed results consistent with a carrier state for muscular dystrophy. Molecular work-up showed the proposita to be a carrier of a deletion mutation of exon 48 of the dystrophin gene. Four male relatives also had the deletion mutation, yet showed no clinical symptoms of muscular dystrophy (age range 8-58 yrs). Linkage analysis of the dystrophin gene in the family showed a spontaneous change of an STR45 allele, which could be due to either an intragenic double recombination event, or CA repeat length mutation leading to identical size alleles. To our knowledge, this is the first documentation of an asymptomatic dystrophinopathy in multiple males of advanced age. Based on molecular findings, this family would be given a diagnosis of Becker muscular dystrophy. This diagnosis implies the development of clinical symptoms, even though this family is clearly asymptomatic. This report underscores the caution which must be exercised when giving presymptomatic diagnoses based on molecular studies. 28 refs., 4 figs., 1 tab.

  3. The Functions of BRCA2 in Homologous Recombinational Repair

    DTIC Science & Technology

    2005-07-01

    expressed the human Rad51 protein in insect cells Sf9 using the baculovirus system. The Rad5I protein was subsequently purified to Fig. 4. Purified...fragment and untagged Rad5 1 B (or Rad5lC) proteins in Sf9 insect cells. We tested BRCI-4/Rad51B, BRC1-8/Rad51B, BRCI-4/Rad51C and BRC 1 -8/Rad5 IC...repeats of BRCA2 and Rad5 I B (or Rad5 1 C) was found. 9 3. The human Rad51 protein was expressed in insect cells and purified to homogeneity using

  4. BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance.

    PubMed

    Jaspers, Janneke E; Sol, Wendy; Kersbergen, Ariena; Schlicker, Andreas; Guyader, Charlotte; Xu, Guotai; Wessels, Lodewyk; Borst, Piet; Jonkers, Jos; Rottenberg, Sven

    2015-02-15

    Pan- or multidrug resistance is a central problem in clinical oncology. Here, we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly resensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel, and doxorubicin. We propose that multidrug resistance is a multifactorial process and that mouse models are useful to unravel this.

  5. Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer

    PubMed Central

    Wappenschmidt, B; Fimmers, R; Rhiem, K; Brosig, M; Wardelmann, E; Meindl, A; Arnold, N; Mallmann, P; Schmutzler, RK

    2005-01-01

    Introduction Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). Methods For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated. Results We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 × 10-8 in favour of neutrality of the variant. Conclusion Our data provide conclusive evidence that the S384F variant is not a disease causing mutation. PMID:16168123

  6. Single-nucleotide polymorphisms in the p53 pathway genes modify cancer risk in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent.

    PubMed

    Yarden, Ronit I; Friedman, Eitan; Metsuyanim, Sally; Olender, Tzvia; Ben-Asher, Edna; Papa, Moshe Z

    2010-06-01

    Germline mutations in the BRCA1 and BRCA2 genes are associated with a significantly increased lifetime risk for developing breast and/or ovarian cancer. However, incomplete penetrance and substantial variability in age of disease onset among carriers of the same mutation suggests the involvement of additional modifier genes and/or environmental factors. Somatic inactivating mutations in the p53 gene and genes of the p53 pathway often accompany BRCA1/2-associated tumors. Therefore, we assessed whether these genes are modifiers of penetrance. We genotyped Jewish-Ashkenazi women for functional single-nucleotide polymorphisms (SNPs) in the AKT1 (C>T rs3730358) and the PERP (C>T rs2484067) genes that affect p53-mediated apoptosis, as well as two tag-SNPs in the CHEK2 (C>T rs743184) and the ZBRK1/ZNF350 (G>A rs2278414) genes that encode for proteins involved in growth arrest following DNA damage. The study population included 138 healthy women, 148 breast/ovarian cancer BRCA1/2 mutation carriers, 121 asymptomatic BRCA1/2 mutation carriers, and 210 sporadic noncarrier breast cancer patients. Utilizing lambda(2) and Kaplan-Meier analysis revealed a hazard ratio (HR) of 3.23 (95% CI: 1.44-54, P = 0.0184) for the TT genotype of AKT (rs3730358), HR = 2.105 (95% CI: 1.049-7.434, P = 0.039) for CHEK2 CC genotype (rs743184), and HR = 2.4743 (95% CI: 1.205-11.53, P = 0.022) for the AG genotype of ZBRK1/ZNF350 (rs2278414). No significant association between PERP variants and cancer was identified HR = 0.662 (95% CI: 0.289-1.324, P = 0.261). Our results suggest that genes that act upstream of p53, or participate in the DNA damage response, may modify the risk of cancer in women with mutant BRCA1/2 alleles.

  7. Susceptibility of BRCA2 Heterozygous Normal Mammary Epithelial Cells to Radiation-Induced Transformation

    DTIC Science & Technology

    2005-10-01

    mouse embryonic fibroblasts (MEF) with less severe BRCA2 truncations (22-24). Particularly, spontaneous accumulation of chromosomal abnormalities ...Scully, R. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells, Mol Cell. 2: 317-28

  8. The complexity of reproductive decision-making in asymptomatic carriers of the Huntington mutation.

    PubMed

    Decruyenaere, Marleen; Evers-Kiebooms, Gerry; Boogaerts, Andrea; Philippe, Kristien; Demyttenaere, Koen; Dom, René; Vandenberghe, Wim; Fryns, Jean-Pierre

    2007-04-01

    The aim of this study was to describe reproductive decisions in mutation carriers after predictive testing for Huntington's disease (HD) and to identify factors that play a role in decision-making. In 1987-2004, 245 individuals received a predictive test result; 89 of them were carriers and seven received an equivocal result. Quantitative data on reproductive behaviour have been collected during all follow-up contacts. The follow-up time in this study was 1-16 years (mean: 7.1 years). Qualitative data on reproductive decision-making have been collected by the means of semistructured interviews during the 5-year follow-up study. For 46 carriers and two persons with an equivocal result, family planning was one of the motives for predictive testing. In this group, slightly more than half of the carriers (58%) had chosen to have children with prenatal diagnosis or preimplantation genetic diagnosis and about one in three (35%) decided to have no children anymore after the test. A minority (7%) was undecided or had no children for other reasons. Factors playing a role in the decision-making process were the carrier's sex, ethical issues about PD and PGD, the strength of the desire to have children, illness representations including personal experiences with HD in the family and the technological imperative. Some of these elements were in conflict and induced ambivalence towards reproductive choices. The results illustrate the complexity of the decision-making process and the necessity of in-depth counselling. Counselling should pay special attention to conflicting values and beliefs and to all kinds of pressure.

  9. Platelet APP isoform ratios in asymptomatic young adults expressing an AD-related presenilin-1 mutation.

    PubMed

    Baskin, F; Rosenberg, R N; Iyer, L; Schellenberg, G D; Hynan, L; Nee, L E

    2001-01-15

    The Alzheimer's disease (AD) related amyloid precursor protein (APP) is stored, cleaved and released similarly from neurons and from platelets. We have reported that the proportion of 120-130 to 110 kDa carboxyl-cleaved APP present in the platelets of AD patients is significantly lower than that of platelets of age-matched controls. This reduced APP isoform ratio, not seen in several other disease groups, is further reduced as the severity of AD increases. Since the neuropathology of AD is believed to begin many years before the onset of cognitive loss, we have also compared platelet APP ratios of four pre-symptomatic young adults carrying a presenilin-1 mutation to seven siblings homozygous for the normal PS-1 gene in an effort to determine whether reduced APP ratios are present before apparent cognitive loss in familial AD. Decreased platelet APP ratios were not seen in any of these subjects at this time. We will continue to monitor these subjects as they near the mean age of AD onset in these families. As the magnitude of the APP ratio reduction is proportional to the severity of cognitive loss in sporadic AD, these cognitively normal incipient AD subjects would not be expected to present significant reductions in this AD severity index at this time. Alternatively, the absence of platelet APP ratio reductions may result from a failure of platelets from familial PS-1 AD subjects to manifest altered APPs, as has been reported for PS-2 AD subjects, unlike those of sporadic AD patients. Continued monitoring of cognitive status in our sub-set of controls with AD-like low APP ratios may yet validate the ability of this assay to detect incipient sporadic AD.

  10. Predictive Factors for BRCA1 and BRCA2 Genetic Testing in an Asian Clinic-Based Population

    PubMed Central

    Wong, Edward S. Y.; Shekar, Sandhya; Chan, Claire H. T.; Hong, Lewis Z.; Poon, Suk-Yean; Silla, Toomas; Lin, Clarabelle; Kumar, Vikrant; Davila, Sonia; Voorhoeve, Mathijs; Thike, Aye Aye; Ho, Gay Hui; Yap, Yoon Sim; Tan, Puay Hoon; Tan, Min-Han; Ang, Peter; Lee, Ann S. G.

    2015-01-01

    Purpose The National Comprehensive Cancer Network (NCCN) has proposed guidelines for the genetic testing of the BRCA1 and BRCA2 genes, based on studies in western populations. This current study assessed potential predictive factors for BRCA mutation probability, in an Asian population. Methods A total of 359 breast cancer patients, who presented with either a family history (FH) of breast and/or ovarian cancer or early onset breast cancer, were accrued at the National Cancer Center Singapore (NCCS). The relationships between clinico-pathological features and mutational status were calculated using the Chi-squared test and binary logistic regression analysis. Results Of 359 patients, 45 (12.5%) had deleterious or damaging missense mutations in BRCA1 and/or BRCA2. BRCA1 mutations were more likely to be found in ER-negative than ER-positive breast cancer patients (P=0.01). Moreover, ER-negative patients with BRCA mutations were diagnosed at an earlier age (40 vs. 48 years, P=0.008). Similarly, triple-negative breast cancer (TNBC) patients were more likely to have BRCA1 mutations (P=0.001) and that these patients were diagnosed at a relatively younger age than non-TNBC patients (38 vs. 46 years, P=0.028). Our analysis has confirmed that ER-negative status, TNBC status and a FH of hereditary breast and ovarian cancer (HBOC) are strong factors predicting the likelihood of having BRCA mutations. Conclusions Our study provides evidence that TNBC or ER-negative patients may benefit from BRCA genetic testing, particularly younger patients (<40 years) or those with a strong FH of HBOC, in Asian patients. PMID:26221963

  11. BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

    PubMed Central

    Meeks, Huong D.; Song, Honglin; Michailidou, Kyriaki; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Barrowdale, Daniel; Frost, Debra; McGuffog, Lesley; Ellis, Steve; Feng, Bingjian; Buys, Saundra S.; Hopper, John L.; Southey, Melissa C.; Tesoriero, Andrea; James, Paul A.; Bruinsma, Fiona; Campbell, Ian G.; Broeks, Annegien; Schmidt, Marjanka K.; Hogervorst, Frans B. L.; Beckman, Matthias W.; Fasching, Peter A.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Riboli, Elio; Banerjee, Susana; Menon, Usha; Tomlinson, Ian; Burwinkel, Barbara; Hamann, Ute; Marme, Frederik; Rudolph, Anja; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Garber, Judy; Cramer, Daniel; Terry, Kathryn L.; Poole, Elizabeth M.; Tworoger, Shelley S.; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Godwin, Andrew K.; Guénel, Pascal; Truong, Thérèse; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M.; Isaacs, Claudine; Maugard, Christine; Bojesen, Stig E.; Flyger, Henrik; Gerdes, Anne-Marie; Hansen, Thomas V. O.; Jensen, Allen; Kjaer, Susanne K.; Hogdall, Claus; Hogdall, Estrid; Pedersen, Inge Sokilde; Thomassen, Mads; Benitez, Javier; González-Neira, Anna; Osorio, Ana; de la Hoya, Miguel; Segura, Pedro Perez; Diez, Orland; Lazaro, Conxi; Brunet, Joan; Anton-Culver, Hoda; Eunjung, Lee; John, Esther M.; Neuhausen, Susan L.; Ding, Yuan Chun; Castillo, Danielle; Weitzel, Jeffrey N.; Ganz, Patricia A.; Nussbaum, Robert L.; Chan, Salina B.; Karlan, Beth Y.; Lester, Jenny; Wu, Anna; Gayther, Simon; Ramus, Susan J.; Sieh, Weiva; Whittermore, Alice S.; Monteiro, Alvaro N. A.; Phelan, Catherine M.; Terry, Mary Beth; Piedmonte, Marion; Offit, Kenneth; Robson, Mark; Levine, Douglas; Moysich, Kirsten B.; Cannioto, Rikki; Olson, Sara H.; Daly, Mary B.; Nathanson, Katherine L.; Domchek, Susan M.; Lu, Karen H.; Liang, Dong; Hildebrant, Michelle A. T.; Ness, Roberta; Modugno, Francesmary; Pearce, Leigh; Goodman, Marc T.; Thompson, Pamela J.; Brenner, Hermann; Butterbach, Katja; Meindl, Alfons; Hahnen, Eric; Wappenschmidt, Barbara; Brauch, Hiltrud; Brüning, Thomas; Blomqvist, Carl; Khan, Sofia; Nevanlinna, Heli; Pelttari, Liisa M.; Aittomäki, Kristiina; Butzow, Ralf; Bogdanova, Natalia V.; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Rantala, Johanna; Kosma, Veli-Matti; Mannermaa, Arto; Lambrechts, Diether; Neven, Patrick; Claes, Kathleen B. M.; Maerken, Tom Van; Chang-Claude, Jenny; Flesch-Janys, Dieter; Heitz, Florian; Varon-Mateeva, Raymonda; Peterlongo, Paolo; Radice, Paolo; Viel, Alessandra; Barile, Monica; Peissel, Bernard; Manoukian, Siranoush; Montagna, Marco; Oliani, Cristina; Peixoto, Ana; Teixeira, Manuel R.; Collavoli, Anita; Hallberg, Emily; Olson, Janet E.; Goode, Ellen L.; Hart, Steven N.; Shimelis, Hermela; Cunningham, Julie M.; Giles, Graham G.; Milne, Roger L.; Healey, Sue; Tucker, Kathy; Haiman, Christopher A.; Henderson, Brian E.; Goldberg, Mark S.; Tischkowitz, Marc; Simard, Jacques; Soucy, Penny; Eccles, Diana M.; Le, Nhu; Borresen-Dale, Anne-Lise; Kristensen, Vessela; Salvesen, Helga B.; Bjorge, Line; Bandera, Elisa V.; Risch, Harvey; Zheng, Wei; Beeghly-Fadiel, Alicia; Cai, Hui; Pylkäs, Katri; Tollenaar, Robert A. E. M.; van der Ouweland, Ans M. W.; Andrulis, Irene L.; Knight, Julia A.; Narod, Steven; Devilee, Peter; Winqvist, Robert; Figueroa, Jonine; Greene, Mark H.; Mai, Phuong L.; Loud, Jennifer T.; García-Closas, Montserrat; Schoemaker, Minouk J.; Czene, Kamila; Darabi, Hatef; McNeish, Iain; Siddiquil, Nadeem; Glasspool, Rosalind; Kwong, Ava; Park, Sue K.; Teo, Soo Hwang; Yoon, Sook-Yee; Matsuo, Keitaro; Hosono, Satoyo; Woo, Yin Ling; Gao, Yu-Tang; Foretova, Lenka; Singer, Christian F.; Rappaport-Feurhauser, Christine; Friedman, Eitan; Laitman, Yael; Rennert, Gad; Imyanitov, Evgeny N.; Hulick, Peter J.; Olopade, Olufunmilayo I.; Senter, Leigha; Olah, Edith; Doherty, Jennifer A.; Schildkraut, Joellen; Koppert, Linetta B.; Kiemeney, Lambertus A.; Massuger, Leon F. A. G.; Cook, Linda S.; Pejovic, Tanja; Li, Jingmei; Borg, Ake; Öfverholm, Anna; Rossing, Mary Anne; Wentzensen, Nicolas; Henriksson, Karin; Cox, Angela; Cross, Simon S.; Pasini, Barbara J.; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Agnarsson, Bjarni A.; Kupryjanczyk, Jolanta; Moes-Sosnowska, Joanna; Fostira, Florentia; Konstantopoulou, Irene; Slager, Susan; Jones, Michael; Antoniou, Antonis C.; Berchuck, Andrew; Swerdlow, Anthony; Chenevix-Trench, Georgia; Dunning, Alison M.; Pharoah, Paul D. P.; Hall, Per; Easton, Douglas F.

    2016-01-01

    Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations. PMID:26586665

  12. DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas

    PubMed Central

    Kamieniak, M M; Muñoz-Repeto, I; Rico, D; Osorio, A; Urioste, M; García-Donas, J; Hernando, S; Robles-Díaz, L; Ramón y Cajal, T; Cazorla, A; Sáez, R; García-Bueno, J M; Domingo, S; Borrego, S; Palacios, J; van de Wiel, M A; Ylstra, B; Benítez, J; García, M J

    2013-01-01

    Background: Few studies have attempted to characterise genomic changes occurring in hereditary epithelial ovarian carcinomas (EOCs) and inconsistent results have been obtained. Given the relevance of DNA copy number alterations in ovarian oncogenesis and growing clinical implications of the BRCA-gene status, we aimed to characterise the genomic profiles of hereditary and sporadic ovarian tumours. Methods: High-resolution array Comparative Genomic Hybridisation profiling of 53 familial (21 BRCA1, 6 BRCA2 and 26 non-BRCA1/2) and 15 sporadic tumours in combination with supervised and unsupervised analysis was used to define common and/or specific copy number features. Results: Unsupervised hierarchical clustering did not stratify tumours according to their familial or sporadic condition or to their BRCA1/2 mutation status. Common recurrent changes, spanning genes potentially fundamental for ovarian carcinogenesis, regardless of BRCA mutations, and several candidate subtype-specific events were defined. Despite similarities, greater contribution of losses was revealed to be a hallmark of BRCA1 and BRCA2 tumours. Conclusion: Somatic alterations occurring in the development of familial EOCs do not differ substantially from the ones occurring in sporadic carcinomas. However, some specific features like extensive genomic loss observed in BRCA1/2 tumours may be of clinical relevance helping to identify BRCA-related patients likely to respond to PARP inhibitors. PMID:23558894

  13. Non-catalytic Roles For XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability

    PubMed Central

    Trego, Kelly S.; Groesser, Torsten; Davalos, Albert R.; Parplys, Ann C.; Zhao, Weixing; Nelson, Michael R.; Hlaing, Ayesu; Shih, Brian; Rydberg, Björn; Pluth, Janice M.; Tsai, Miaw-Sheue; Hoeijmakers, Jan H.J.; Sung, Patrick; Wiese, Claudia; Campisi, Judith; Cooper, Priscilla K.

    2016-01-01

    SUMMARY XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective Xpg mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging. PMID:26833090

  14. BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine.

    PubMed

    Jones, Rebecca M; Kotsantis, Panagiotis; Stewart, Grant S; Groth, Petra; Petermann, Eva

    2014-10-01

    Replication inhibitors cause replication fork stalling and double-strand breaks (DSB) that result from processing of stalled forks. During recovery from replication blocks, the homologous recombination (HR) factor RAD51 mediates fork restart and DSB repair. HR defects therefore sensitize cells to replication inhibitors, with clear implications for cancer therapy. Gemcitabine is a potent replication inhibitor used to treat cancers with mutations in HR genes such as BRCA2. Here, we investigate why, paradoxically, mutations in HR genes protect cells from killing by gemcitabine. Using DNA replication and DNA damage assays in mammalian cells, we show that even short gemcitabine treatments cause persistent replication inhibition. BRCA2 and RAD51 are recruited to chromatin early after removal of the drug, actively inhibit replication fork progression, and promote the formation of MUS81- and XPF-dependent DSBs that remain unrepaired. Our data suggest that HR intermediates formed at gemcitabine-stalled forks are converted into DSBs and thus contribute to gemcitabine-induced cell death, which could have implications for the treatment response of HR-deficient tumors.

  15. Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.

    PubMed

    Trego, Kelly S; Groesser, Torsten; Davalos, Albert R; Parplys, Ann C; Zhao, Weixing; Nelson, Michael R; Hlaing, Ayesu; Shih, Brian; Rydberg, Björn; Pluth, Janice M; Tsai, Miaw-Sheue; Hoeijmakers, Jan H J; Sung, Patrick; Wiese, Claudia; Campisi, Judith; Cooper, Priscilla K

    2016-02-18

    XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging.

  16. MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

    PubMed Central

    Jiang, Qinqin; Paramasivam, Manikandan; Aressy, Bernadette; Wu, Junmin; Bellani, Marina; Tong, Wei; Seidman, Michael M.; Greenberg, Roger A.

    2015-01-01

    MERIT40 is an essential component of the RAP80 ubiquitin recognition complex that targets BRCA1 to DNA damage sites. Although this complex is required for BRCA1 foci formation, its physiologic role in DNA repair has remained enigmatic, as has its relationship to canonical DNA repair mechanisms. Surprisingly, we found that Merit40−/− mice displayed marked hypersensitivity to DNA interstrand cross-links (ICLs) but not whole-body irradiation. MERIT40 was rapidly recruited to ICL lesions prior to FANCD2, and Merit40-null cells exhibited delayed ICL unhooking coupled with reduced end resection and homologous recombination at ICL damage. Interestingly, Merit40 mutation exacerbated ICL-induced chromosome instability in the context of concomitant Brca2 deficiency but not in conjunction with Fancd2 mutation. These findings implicate MERIT40 in the earliest stages of ICL repair and define specific functional interactions between RAP80 complex-dependent ubiquitin recognition and the Fanconi anemia (FA)–BRCA ICL repair network. PMID:26338419

  17. Association of the germline BRCA2 missense variation Glu2663Lys with high sensitivity to trabectedin-based treatment in soft tissue sarcoma.

    PubMed

    Miolo, Gianmaria; Viel, Alessandra; Canzonieri, Vincenzo; Baresic, Tania; Buonadonna, Angela; Santeufemia, Davide Adriano; Lara, Della Puppa; Corona, Giuseppe

    2016-10-02

    We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only 3 cycles of trabectedin treatment (1.5 mg/m(2) given intravenously over 24 hours every 21 days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy.

  18. Localization of human BRCA1 and BRCA2 in non-inherited colorectal carcinomas and matched normal mucosas.

    PubMed

    Bernard-Gallon, D J; Peffault de Latour, M; Hizel, C; Vissac, C; Cure, H; Pezet, D; Dechelotte, P J; Chipponi, J; Chassagne, J; Bignon, Y J

    2001-01-01

    We characterized the expression of BRCA1 and BRCA2 in 38 sporadic colorectal carcinomas and matched normal mucosas with 9 anti-BRCA1 antibodies and 4 anti-BRCA2 antibodies, raised against several different epitopes, using immunohistochemical technique. We demonstrated an increased BRCA1 and BRCA2 staining in the apical cell pole of epithelial malignant cells and we also revealed a significant increase in BRCA1 and BRCA2 nuclear foci in tumor colorectal specimens in comparison with corresponding normal tissues. These increases in BRCA1 and BRCA2 expression may be explained by the fact that colorectal tissue is subject to very active proliferation and differentiation.

  19. BRCA1/2 germline mutations and their clinical importance in Turkish breast cancer patients.

    PubMed

    Cecener, Gulsah; Egeli, Unal; Tunca, Berrin; Erturk, Elif; Ak, Secil; Gokgoz, Sehsuvar; Tasdelen, Ismet; Tezcan, Gulcin; Demirdogen, Elif; Bayram, Nuran; Avci, Nilufer; Evrensel, Turkkan

    2014-10-01

    BRCA1/BRCA2 genes were screened in 117 patients with breast cancer by sequencing. Fourteen percent of patients tested positive for BRCA1/BRCA2 mutations. Four frame shift mutations, four pathogenic missense mutations, and 25 different sequence variations were detected. BRCA mutation positivity was significantly associated with Ki67 (p = .001). BRCA protein expressions were decreased in the patients harboring important mutations and polymorphisms (BRCA1;P508 stop, V1740G, Q1182R, Q1756P and BRCA2;V2466A) related with disease. Our findings contribute significantly to the types of germline BRCA1/BRCA2 mutations and their biological effects in Turkish women. These data could help guide the management of BRCA1/BRCA2 mutation-carrying patients when considering breast-conserving therapy.

  20. BRCA2-dependent homologous recombination is required for repair of Arsenite-induced replication lesions in mammalian cells

    PubMed Central

    Ying, Songmin; Myers, Katie; Bottomley, Sarah; Helleday, Thomas; Bryant, Helen E.

    2009-01-01

    Arsenic exposure constitutes one of the most widespread environmental carcinogens, and is associated with increased risk of many different types of cancers. Here we report that arsenite (As[III]) can induce both replication-dependent DNA double-strand breaks (DSB) and homologous recombination (HR) at doses as low as 5 µM (0.65 mg/l), which are within the typical doses often found in drinking water in contaminated areas. We show that the production of DSBs is dependent on active replication and is likely to be the result of conversion of a DNA single-strand break (SSB) into a toxic DSB when encountered by a replication fork. We demonstrate that HR is required for the repair of these breaks and show that a functional HR pathway protects against As[III]-induced cytotoxicity. In addition, BRCA2-deficient cells are sensitive to As[III] and we suggest that As[III] could be exploited as a therapy for HR-deficient tumours such as BRCA1 and BRCA2 mutated breast and ovarian cancers. PMID:19553191

  1. Disruption of Brca2-Rad51 Complex in Breast Cancer Cells: Therapeutic Implications

    DTIC Science & Technology

    2005-09-01

    Rad51B, Rad51 C, Rad51D,Xrcc2and Xrcc3 ) and the breast cancer associated proteins,BRCAI and BRCA2. Defective cell lines in each of the above...Aloyz recombination from the structure of a RAD5 I-BRCA2 complex. Nature 2002, 420, 287-293. 5. Xu ZY, Loignon M, Han FY, Panasci L, Aloyz R.. Xrcc3

  2. BRCA2 hypomorphic missense variants confer moderate risks of breast cancer.

    PubMed

    Shimelis, Hermela; Mesman, Romy L S; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calleja, Fabienne Mgr; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M; Aittomaki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W; Benitez, Javier J; Bogdanova, Natalia; Bojesen, Stig E; Bolla, Manjeet K; Borresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Brouwers, Barbara; Bruning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Cheng, Ching-Yu; Choi, Ji-Yeob; Collée, J Margriet; Cox, Angela; Cross, Simon S; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Dork, Thilo; Dos Santos Silva, Isabel; Dunning, Alison M; Fasching, Peter A; Figueroa, Jonine D; Flyger, Henrik; Garcia-Closas, Montserrat; Giles, Graham G; Glendon, Gord; Guenel, Pascal; Haiman, Christopher A; Hall, Per; Hamann, Ute; Hartman, Mikael; Hogervorst, Frans B L; Hollestelle, Antoinette; Hopper, John L; Ito, Hidemi; Jakubowska, Anna; Kang, Daehee; Kosma, Veli-Matti; Kristensen, Vessela; Lai, Kah-Nyin; Lambrechts, Diether; Le Marchand, Loic; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Machackova, Eva; Mannermaa, Arto; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; Miao, Hui; Michailidou, Kyriaki; Milne, Roger L; Muir, Kenneth; Neuhausen, Susan L; Nevanlinna, Heli; Olson, Janet E; Olswold, Curtis; Oosterwijk, Jan C; Osorio, Ana; Peterlongo, Paolo; Peto, Julian; Pharoah, Paul D P; Pylkäs, Katri; Radice, Paolo; Rashid, Muhammad U; Rhenius, Valerie; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Marjanka K; Schoemaker, Minouk J; Seynaeve, Caroline M; Shah, Mitul; Shen, Chen-Yang; Shrubsole, Martha J; Shu, Xiao-Ou; Slager, Susan L; Southey, Melissa C; Stram, Daniel O; Swerdlow, Anthony J; Teo, Soo Hwang; Tomlinson, Ian; Torres, Diana; Truong, Therese; van Asperen, Christi J; van der Kolk, Lizet E; Wang, Qin; Winqvist, Robert; Wu, Anna H; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Leary, Jennifer; Walker, Logan C; Foretova, Lenka; Fostira, Florentia; Claes, Kathleen; Varesco, Liliana; Moghadasi, Setareh; Easton, Douglas F; Spurdle, Amanda B; Devilee, Peter; Vrieling, Harry; Monteiro, Alvaro N; Goldgar, David E; Carreira, Aura; Vreeswijk, Maaike P G; Couch, Fergus J

    2017-03-10

    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR=2.52, p=0.04) and BRCA1 c.5096G>A, p.Arg1699Gln (OR=4.29, p=0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR=2.68, p=0.004) and c.8187G>T, p.Lys2729Asn (OR=1.4, p=0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared to wildtype. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants.

  3. Interference with BRCA2, which localizes to the centrosome during S and early M phase, leads to abnormal nuclear division

    SciTech Connect

    Nakanishi, Akira; Han, Xiangzi; Saito, Hiroko; Taguchi, Keiko; Ohta, Yoshiyasu; Imajoh-Ohmi, Shinobu; Miki, Yoshio; E-mail: miki.mgen@mri.tmd.ac.jp

    2007-03-30

    BRCA2 is responsible for familial breast and ovarian cancer, and its gene product is linked to DNA repair and transcriptional regulation. The BRCA2 protein exists mainly in the nucleus. Here, we show that BRCA2 has a centrosomal localization signal (CLS), localizes also to centrosomes during S and early M phases, and may regulate duplication and separation of the centrosomes. Green fluorescent protein (GFP) fused to the CLS peptides from BRCA2 (GFP-CLS) localizes to centrosomes and prevents endogenous BRCA2 from localizing to centrosomes. In addition, expression of GFP-CLS in cells leads to the abnormal duplication and positioning of centrosomes, resulting in the generation of multinuclear cells. These results thus implicate BRCA2 in the regulation of the centrosome cycle, and provide new insight into the aneuploid nature of many breast cancers.

  4. Large genomic rearrangements of BRCA1 and BRCA2 among patients referred for genetic analysis in Galicia (NW Spain): delimitation and mechanism of three novel BRCA1 rearrangements.

    PubMed

    Fachal, Laura; Blanco, Ana; Santamariña, Marta; Carracedo, Angel; Vega, Ana

    2014-01-01

    In the Iberian Peninsula, which includes mainly Spain and Portugal, large genomic rearrangements (LGRs) of BRCA1 and BRCA2 have respectively been found in up to 2.33% and 8.4% of families with hereditary breast and/or ovarian cancer (HBOC) that lack point mutations and small indels. In Galicia (Northwest Spain), the spectrum and frequency of BRCA1/BRCA2 point mutations differs from the rest of the Iberian populations. However, to date there are no Galician frequency reports of BRCA1/BRCA2 LGRs. Here we used multiplex ligation-dependent probe amplification (MLPA) to screen 651 Galician index cases (out of the 830 individuals referred for genetic analysis) without point mutations or small indels. We identified three different BRCA1 LGRs in four families. Two of them have been previously classified as pathogenic LGRs: the complete deletion of BRCA1 (identified in two unrelated families) and the deletion of exons 1 to 13. We also identified the duplication of exons 1 and 2 that is a LGR with unknown pathogenicity. Determination of the breakpoints of the BRCA1 LGRs using CNV/SNP arrays and sequencing identified them as NG_005905.2:g.70536_180359del, NG_005905.2:g.90012_97270dup, and NC_000017.10:g.41230935_41399840delinsAluSx1, respectively; previous observations of BRCA1 exon1-24del, exon1-2dup, and exon1-13del LGRs have not characterized them in such detail. All the BRCA1 LGRs arose from unequal homologous recombination events involving Alu elements. We also detected, by sequencing, one BRCA2 LGR, the Portuguese founder mutation c.156_157insAluYa5. The low frequency of BRCA1 LGRs within BRCA1 mutation carriers in Galicia (2.34%, 95% CI: 0.61-7.22) seems to differ from the Spanish population (9.93%, 95% CI: 6.76-14.27, P-value = 0.013) and from the rest of the Iberian population (9.76%, 95% CI: 6.69-13.94, P-value = 0.014).

  5. Asymptomatic bacteriuria

    MedlinePlus

    ... you have these symptoms, you may have a urinary tract infection but you DO NOT have asymptomatic bacteriuria. Burning ... the future. However, for some people getting a urinary tract infection is more likely or may cause more severe ...

  6. Genetic variations of BRCA1 and BRCA2 genes in dogs with mammary tumours.

    PubMed

    Enginler, S O; Akış, I; Toydemir, T S F; Oztabak, K; Haktanir, D; Gündüz, M C; Kırşan, I; Fırat, I

    2014-03-01

    Mammary tumours are the most common tumour type in female dogs. The formation of the mammary tumours is multifactorial but the high incidence of tumour disease in certain canine breeds suggests a strong genetic component. BRCA1 and BRCA2 are the most important genes significantly associated with mammary tumours. The aim of this study was to determine the association between the variations of these two genes and canine mammary tumours. 5'-untranslated region, intron 8 and exon 9 of BRCA1 and exons 12, 24, 27 of BRCA2 were sequenced in order to detect the genetic variations. In addition to six previously identified polymorphisms, six novel single nucleotide polymorphisms (SNPs) were detected. Five of the coding SNPs were synonymous and three of them were non-synonymous. The comparison of the sequences from 25 mammary tumour bearing and 10 tumour free dogs suggested that the two SNPs in intron 8 and exon 9 of BRCA1 and two SNPs in exon 24 and exon 27 of BRCA2, which are firstly identified in this study, might be associated with mammary tumour development in dogs. Especially one SNP in exon 9 of BRCA1 and one SNP in exon 24 of BRCA2 were found to be significantly associated with canine mammary tumours.

  7. Genetic variations of BRCA1 and BRCA2 genes in dogs with mammary tumours.

    PubMed

    Enginler, S O; Akış, I; Toydemir, T S F; Oztabak, K; Haktanir, D; Gündüz, M C; Kırşan, I; Fırat, I

    2014-03-01

    Mammary tumours are the most common tumour type in female dogs. The formation of the mammary tumours is multifactorial but the high incidence of tumour disease in certain canine breeds suggests a strong genetic component. BRCA1 and BRCA2 are the most important genes significantly associated with mammary tumours. The aim of this study was to determine the association between the variations of these two genes and canine mammary tumours. 5′-untranslated region, intron 8 and exon 9 of BRCA1 and exons 12, 24, 27 of BRCA2 were sequenced in order to detect the genetic variations. In addition to six previously identified polymorphisms, six novel single nucleotide polymorphisms (SNPs) were detected. Five of the coding SNPs were synonymous and three of them were non-synonymous. The comparison of the sequences from 25 mammary tumour bearing and 10 tumour free dogs suggested that the two SNPs in intron 8 and exon 9 of BRCA1 and two SNPs in exon 24 and exon 27 of BRCA2, which are firstly identified in this study, might be associated with mammary tumour development in dogs. Especially one SNP in exon 9 of BRCA1 and one SNP in exon 24 of BRCA2 were found to be significantly associated with canine mammary tumours.

  8. Histologic and Immunohistochemical Analyses of Soft Tissue Sarcomas From brca2-Mutant/ tp53-Mutant Zebrafish Are Consistent With Neural Crest (Schwann Cell) Origin.

    PubMed

    White, L A; Sexton, J M; Shive, H R

    2017-03-01

    The zebrafish ( Danio rerio) provides a powerful model for analyzing genetic contributors to cancer. Multiple zebrafish lines with cancer-associated genetic mutations develop soft tissue sarcomas that are histologically consistent with malignant peripheral nerve sheath tumor (MPNST). The goal of this study was to determine the phenotype of soft tissue sarcomas in a brca2-mutant/ tp53-mutant zebrafish line using immunohistochemical markers that are commonly expressed in mammalian MPNST. We classified 70 soft tissue sarcomas from a brca2-mutant/ tp53-mutant zebrafish cohort as MPNST, undifferentiated sarcoma, or other tumor based on histologic features. The expression of S100, CD57, and glial fibrillary acidic protein (GFAP) was analyzed in nonneoplastic neural tissues and tumor specimens by immunohistochemistry. Each marker was expressed in nonneoplastic neural tissues. In MPNST, S100 and CD57 were widely expressed in neoplastic cells, with greater consistency observed for CD57 expression. In undifferentiated sarcomas, results were variable and correlated to anatomic location. Coelomic undifferentiated sarcomas often exhibited widespread CD57 expression but limited S100 expression. In comparison, ocular undifferentiated sarcomas exhibited limited expression of both CD57 and S100. Overall, CD57 and S100 expression was significantly higher in MPNST than in undifferentiated sarcomas. GFAP was not expressed in any of the tumors. This study identified commercially available antibodies that are useful for analyzing S100, CD57, and GFAP expression in zebrafish. This study further shows a correlation between degree of histologic differentiation and expression of these markers in soft tissue sarcomas from brca2-mutant/ tp53-mutant zebrafish and suggests that these cancers are derived from the neural crest with differentiation toward myelinating Schwann cells.

  9. The Functions of BRCA2 in Homologous Recombinational Repair

    DTIC Science & Technology

    2004-07-01

    February 2004. 2. A manuscript related to this project entitled "Human Rad51C deficiency destabilizes XRCC3 , impairs recombination and radiosensitizes...Cell Biol 15: 1968-1973 15. Brenneman MA et al. (2000) XRCC3 is required for efficient repair of chromosome breaks by homologous recombination. Mutat...JBiol Chem 278: 2469-2478 APPENDICES 1. Lio, Y-C, Schild, D, Brenneman, MA, Redpath, JL, and Chen, DJ (2004) Human RadS1C deficiency destabilizes XRCC3

  10. BRCA2 diffuses as oligomeric clusters with RAD51 and changes mobility after DNA damage in live cells

    PubMed Central

    Reuter, Marcel; Zelensky, Alex; Smal, Ihor; Meijering, Erik; van Cappellen, Wiggert A.; de Gruiter, H. Martijn; van Belle, Gijsbert J.; van Royen, Martin E.; Houtsmuller, Adriaan B.; Essers, Jeroen; Kanaar, Roland

    2014-01-01

    Genome maintenance by homologous recombination depends on coordinating many proteins in time and space to assemble at DNA break sites. To understand this process, we followed the mobility of BRCA2, a critical recombination mediator, in live cells at the single-molecule level using both single-particle tracking and fluorescence correlation spectroscopy. BRCA2-GFP and -YFP were compared to distinguish diffusion from fluorophore behavior. Diffusive behavior of fluorescent RAD51 and RAD54 was determined for comparison. All fluorescent proteins were expressed from endogenous loci. We found that nuclear BRCA2 existed in oligomeric clusters, and exhibited heterogeneous mobility. DNA damage increased BRCA2 transient binding, presumably including binding to damaged sites. Despite its very different size, RAD51 displayed mobility similar to BRCA2, which indicates physical interaction between these proteins both before and after induction of DNA damage. We propose that BRCA2-mediated sequestration of nuclear RAD51 serves to prevent inappropriate DNA interactions and that all RAD51 is delivered to DNA damage sites in association with BRCA2. PMID:25488918

  11. New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study

    PubMed Central

    Plaskocinska, Inga; Shipman, Hannah; Drummond, James; Thompson, Edward; Buchanan, Vanessa; Newcombe, Barbara; Hodgkin, Charlotte; Barter, Elisa; Ridley, Paul; Ng, Rita; Miller, Suzanne; Dann, Adela; Licence, Victoria; Webb, Hayley; Tan, Li Tee; Daly, Margaret; Ayers, Sarah; Rufford, Barnaby; Earl, Helena; Parkinson, Christine; Duncan, Timothy; Jimenez-Linan, Mercedes; Sagoo, Gurdeep S; Abbs, Stephen; Hulbert-Williams, Nicholas; Pharoah, Paul; Crawford, Robin; Brenton, James D; Tischkowitz, Marc

    2016-01-01

    Background Over recent years genetic testing for germline mutations in BRCA1/BRCA2 has become more readily available because of technological advances and reducing costs. Objective To explore the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (EOC). Methods Between 1 July 2013 and 30 June 2015 women newly diagnosed with EOC were recruited through six sites in East Anglia, UK into the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. Eligibility was irrespective of patient age and family history of cancer. The psychosocial arm of the study used self-report, psychometrically validated questionnaires (Depression Anxiety and Stress Scale (DASS-21); Impact of Event Scale (IES)) and cost analysis was performed. Results 232 women were recruited and 18 mutations were detected (12 in BRCA1, 6 in BRCA2), giving a mutation yield of 8%, which increased to 12% in unselected women aged <70 years (17/146) but was only 1% in unselected women aged ≥70 years (1/86). IES and DASS-21 scores in response to genetic testing were significantly lower than equivalent scores in response to cancer diagnosis (p<0.001). Correlation tests indicated that although older age is a protective factor against any traumatic impacts of genetic testing, no significant correlation exists between age and distress outcomes. Conclusions The mutation yield in unselected women diagnosed with EOC from a heterogeneous population with no founder mutations was 8% in all ages and 12% in women under 70. Unselected genetic testing in women with EOC was acceptable to patients and is potentially less resource-intensive than current standard practice. PMID:27208206

  12. Evaluation of genetic variations in miRNA-binding sites of BRCA1 and BRCA2 genes as risk factors for the development of early-onset and/or familial breast cancer.

    PubMed

    Erturk, Elif; Cecener, Gulsah; Polatkan, Volkan; Gokgoz, Sehsuvar; Egeli, Unal; Tunca, Berrin; Tezcan, Gulcin; Demirdogen, Elif; Ak, Secil; Tasdelen, Ismet

    2014-01-01

    Although genetic markers identifying women at an increased risk of developing breast cancer exist, the majority of inherited risk factors remain elusive. Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intron- exon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/ BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. Two polymorphisms were identified. SNPs c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In comparison to variations in the 3'UTR region of the BRCA1/2 genes and the BRCA1/2 mutational status in patients, there was a statistically significant relationship between the BRCA1 gene polymorphism c.*1287C>T (rs12516) and BRCA1 mutations (p=0.035) by Fisher's Exact Test. SNP c.*1287C>T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased early-onset and/or familial breast cancer risk in the Turkish population.

  13. BRCA2 coordinates the activities of cell-cycle kinases to promote genome stability.

    PubMed

    Yata, Keiko; Bleuyard, Jean-Yves; Nakato, Ryuichiro; Ralf, Christine; Katou, Yuki; Schwab, Rebekka A; Niedzwiedz, Wojciech; Shirahige, Katsuhiko; Esashi, Fumiko

    2014-06-12

    Numerous human genome instability syndromes, including cancer, are closely associated with events arising from malfunction of the essential recombinase Rad51. However, little is known about how Rad51 is dynamically regulated in human cells. Here, we show that the breast cancer susceptibility protein BRCA2, a key Rad51 binding partner, coordinates the activity of the central cell-cycle drivers CDKs and Plk1 to promote Rad51-mediated genome stability control. The soluble nuclear fraction of BRCA2 binds Plk1 directly in a cell-cycle- and CDK-dependent manner and acts as a molecular platform to facilitate Plk1-mediated Rad51 phosphorylation. This phosphorylation is important for enhancing the association of Rad51 with stressed replication forks, which in turn protects the genomic integrity of proliferating human cells. This study reveals an elaborate but highly organized molecular interplay between Rad51 regulators and has significant implications for understanding tumorigenesis and therapeutic resistance in patients with BRCA2 deficiency.

  14. Brca2-Pds5 complexes mobilize persistent meiotic recombination sites to the nuclear envelope.

    PubMed

    Kusch, Thomas

    2015-02-15

    Homologous recombination is required for reciprocal exchange between homologous chromosome arms during meiosis. Only select meiotic recombination events become chromosomal crossovers; the majority of recombination outcomes are noncrossovers. Growing evidence suggests that crossovers are repaired after noncrossovers. Here, I report that persisting recombination sites are mobilized to the nuclear envelope of Drosophila pro-oocytes during mid-pachytene. Their number correlates with the average crossover rate per meiosis. Proteomic and interaction studies reveal that the recombination mediator Brca2 associates with lamin and the cohesion factor Pds5 to secure persistent recombination sites at the nuclear envelope. In Rad51(-/-) females, all persistent DNA breaks are directed to the nuclear envelope. By contrast, a reduction of Pds5 or Brca2 levels abolishes the movement and has a negative impact on crossover rates. The data suggest that persistent meiotic DNA double-strand breaks might correspond to crossovers, which are mobilized to the nuclear envelope for their repair. The identification of Brca2-Pds5 complexes as key mediators of this process provides a first mechanistic explanation for the contribution of lamins and cohesins to meiotic recombination.

  15. A nucleolytic lupus autoantibody is toxic to BRCA2-deficient cancer cells

    PubMed Central

    Noble, Philip W.; Young, Melissa R.; Bernatsky, Sasha; Weisbart, Richard H.; Hansen, James E.

    2014-01-01

    Cancer cells with defects in DNA repair are highly susceptible to DNA-damaging agents, but delivery of therapeutic agents into cell nuclei can be challenging. A subset of lupus autoantibodies is associated with nucleolytic activity, and some of these antibodies are capable of nuclear penetration. We hypothesized that such antibodies might have potential as therapeutic agents targeted towards DNA repair-deficient malignancies. We identified the lupus autoantibody 5C6 as a cell-penetrating nucleolytic antibody and found that 5C6 has a differential effect on a matched pair of BRCA2-proficient and deficient DLD1 colon cancer cells. 5C6 selectively induced γH2AX in, and suppressed the growth of, the BRCA2-deficient cells. These findings demonstrate the potential utility of 5C6 in targeted therapy for DNA repair-deficient malignancies and strengthen the rationale for studies of additional lupus autoantibodies in order to identify the best candidates for development as therapeutic agents. In addition, the toxic effect of 5C6 on BRCA2-deficient cells provides further support for the hypothesis that some lupus autoantibodies contribute to the lower risk of specific cancers associated with systemic lupus erythematosus. PMID:25091037

  16. FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3.

    PubMed

    Wilson, J B; Yamamoto, K; Marriott, A S; Hussain, S; Sung, P; Hoatlin, M E; Mathew, C G; Takata, M; Thompson, L H; Kupfer, G M; Jones, N J

    2008-06-12

    Fanconi anemia (FA) is a human disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. Thirteen complementation groups and genes are identified, including BRCA2, which is defective in the FA-D1 group. Eight of the FA proteins, including FANCG, participate in a nuclear core complex that is required for the monoubiquitylation of FANCD2 and FANCI. FANCD2, like FANCD1/BRCA2, is not part of the core complex, and we previously showed direct BRCA2-FANCD2 interaction using yeast two-hybrid analysis. We now show in human and hamster cells that expression of FANCG protein, but not the other core complex proteins, is required for co-precipitation of BRCA2 and FANCD2. We also show that phosphorylation of FANCG serine 7 is required for its co-precipitation with BRCA2, XRCC3 and FANCD2, as well as the direct interaction of BRCA2-FANCD2. These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). Cells that fail to express either phospho-Ser7-FANCG, or full length BRCA2 protein, lack the interactions amongst the four component proteins. A role for D1-D2-G-X3 in homologous recombination repair (HRR) is supported by our finding that FANCG and the RAD51-paralog XRCC3 are epistatic for sensitivity to DNA crosslinking compounds in DT40 chicken cells. Our findings further define the intricate interface between FANC and HRR proteins in maintaining chromosome stability.

  17. Cisplatin With or Without Veliparib in Treating Patients With Stage IV Triple-Negative and/or BRCA Mutation-Associated Breast Cancer

    ClinicalTrials.gov

    2017-04-11

    BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Breast Carcinoma Metastatic in the Brain; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  18. Development and characterization of reference materials for MTHFR, SERPINA1, RET, BRCA1, and BRCA2 genetic testing.

    PubMed

    Barker, Shannon D; Bale, Sherri; Booker, Jessica; Buller, Arlene; Das, Soma; Friedman, Kenneth; Godwin, Andrew K; Grody, Wayne W; Highsmith, Edward; Kant, Jeffery A; Lyon, Elaine; Mao, Rong; Monaghan, Kristin G; Payne, Deborah A; Pratt, Victoria M; Schrijver, Iris; Shrimpton, Antony E; Spector, Elaine; Telatar, Milhan; Toji, Lorraine; Weck, Karen; Zehnbauer, Barbara; Kalman, Lisa V

    2009-11-01

    Well-characterized reference materials (RMs) are integral in maintaining clinical laboratory quality assurance for genetic testing. These RMs can be used for quality control, monitoring of test performance, test validation, and proficiency testing of DNA-based genetic tests. To address the need for such materials, the Centers for Disease Control and Prevention established the Genetic Testing Reference Material Coordination Program (GeT-RM), which works with the genetics community to improve public availability of characterized RMs for genetic testing. To date, the GeT-RM program has coordinated the characterization of publicly available genomic DNA RMs for a number of disorders, including cystic fibrosis, Huntington disease, fragile X, and several genetic conditions with relatively high prevalence in the Ashkenazi Jewish population. Genotypic information about a number of other cell lines has been collected and is also available. The present study includes the development and commutability/genotype characterization of 10 DNA samples for clinically relevant mutations or sequence variants in the following genes: MTHFR; SERPINA1; RET; BRCA1; and BRCA2. DNA samples were analyzed by 19 clinical genetic laboratories using a variety of assays and technology platforms. Concordance was 100% for all samples, with no differences observed between laboratories using different methods. All DNA samples are available from Coriell Cell Repositories and characterization information can be found on the GeT-RM website.

  19. Endogenous levels of Rad51 and Brca2 are required for homologous recombination and regulated by homeostatic re-balancing.

    PubMed

    Magwood, Alissa C; Malysewich, Michael J; Cealic, Iulia; Mundia, Maureen M; Knapp, Jennifer; Baker, Mark D

    2013-12-01

    Stable expression of Rad51 siRNA was used to generate mouse hybridoma cell lines in which endogenous Rad51 levels were depleted by as much as 60%. Stable Rad51 knockdowns feature reduced homologous recombination responses. The relative ease with which stable Rad51 knockdowns were recovered was surprising, given the embryonic lethality of Rad51 ablation. Interestingly, Rad51-depleted hybridoma cell lines are characterized by reduced levels of p53 protein. Completely unexpected, was the finding that Rad51-depleted hybridoma cell lines are also reduced for the breast cancer susceptibility 2 (Brca2) protein. Additionally, hybridoma cell lines that are siRNA depleted for mouse Brca2 show a corresponding reduction in Rad51 and p53 proteins. Furthermore, cellular levels of Rad51, Brca2 and p53 can be elevated in these cell lines by ectopic expression of wild-type human Rad51 and wild-type human BRCA2. In marked contrast, hybridoma cell lines that are siRNA depleted for mouse p53 feature relatively normal Rad51 and Brca2 levels. These results suggest that cellular levels of Brca2 and Rad51 are mutually dependent on each other, and that low levels of these proteins provide selective pressure for reduction of p53, which permits cell growth.

  20. Several tetratricopeptide repeat (TPR) motifs of FANCG are required for assembly of the BRCA2/D1-D2-G-X3 complex, FANCD2 monoubiquitylation and phleomycin resistance.

    PubMed

    Wilson, James B; Blom, Eric; Cunningham, Ryan; Xiao, Yuxuan; Kupfer, Gary M; Jones, Nigel J

    2010-07-07

    The Fanconi anaemia (FA) FANCG protein is an integral component of the FA nuclear core complex that is required for monoubiquitylation of FANCD2. FANCG is also part of another protein complex termed D1-D2-G-X3 that contains FANCD2 and the homologous recombination repair proteins BRCA2 (FANCD1) and XRCC3. Formation of the D1-D2-G-X3 complex is mediated by serine-7 phosphorylation of FANCG and occurs independently of the FA core complex and FANCD2 monoubiquitylation. FANCG contains seven tetratricopeptide repeat (TPR) motifs that mediate protein-protein interactions and here we show that mutation of several of the TPR motifs at a conserved consensus residue ablates the in vivo binding activity of FANCG. Expression of mutated TPR1, TPR2, TPR5 and TPR6 in Chinese hamster fancg mutant NM3 fails to functionally complement its hypersensitivities to mitomycin C (MMC) and phleomycin and fails to restore FANCD2 monoubiquitylation. Using co-immunoprecipitation analysis, we demonstrate that these TPR-mutated FANCG proteins fail to interact with BRCA2, XRCC3, FANCA or FANCF. The interactions of other proteins in the D1-D2-G-X3 complex are also absent, including the interaction of BRCA2 with both the monoubiquitylated (FANCD2-L) and non-ubiquitylated (FANCD2-S) isoforms of FANCD2. Interestingly, a mutation of TPR7 (R563E), that complements the MMC and phleomycin hypersensitivity of human FA-G EUFA316 cells, fails to complement NM3, despite the mutated FANCG protein co-precipitating with FANCA, BRCA2 and XRCC3. Whilst interaction of TPR7-mutated FANCG with FANCF does appear to be reduced in NM3, FANCD2 is monoubiquitylated suggesting that sub-optimal interactions of FANCG in the core complex and the D1-D2-G-X3 complex are responsible for the observed MMC- and phleomycin-hypersensitivity, rather than a defect in FANCD2 monoubiquitylation. Our data demonstrate that FANCG functions as a mediator of protein-protein interactions and is vital for the assembly of multi-protein complexes

  1. Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction.

    PubMed

    Zhi, Gang; Wilson, James B; Chen, Xiaoyong; Krause, Diane S; Xiao, Yuxuan; Jones, Nigel J; Kupfer, Gary M

    2009-11-15

    Fanconi anemia is a cancer-prone inherited bone marrow failure and cancer susceptibility syndrome with at least 13 complementation groups (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN). Our laboratory has previously described several regulatory phosphorylation events for core complex member proteins FANCG and FANCA by phosphorylation. In this study, we report a novel phosphorylation site serine 331 (S331) of FANCD2, the pivotal downstream player of the Fanconi anemia pathway. Phosphorylation of S331 is important for its DNA damage-inducible monoubiquitylation, resistance to DNA cross-linkers, and in vivo interaction with FANCD1/BRCA2. A phosphomimetic mutation at S331 restores all of these phenotypes to wild-type. In vitro and in vivo experiments show that phosphorylation of S331 is mediated by CHK1, the S-phase checkpoint kinase implicated in the Fanconi anemia DNA repair pathway.

  2. Molecular Basis for BRCA2-mediated DNA Repair and Breast Tumor Suppression

    DTIC Science & Technology

    2009-10-01

    breaks are mediated by the RAD51 recombinase . In catalyzing recombination reactions, RAD51 must first form a right-handed helical filament, termed the...analogs and poly(ADP-ribose) polymerase inhibitors, exploit the incapability of BRCA2-deficient cells to rely on HR for the repair of DSBs. Apparently...Instability and DNA repair in Taos, New Mexico (March 1-5, 2009). I am a coauthor on manuscript “Enhancement of the RAD51 Recombinase by the Tumor Suppressor

  3. Disruption of Brca2-Rad51 Complex in Breast Cancer Cells: Therapeutic Implications

    DTIC Science & Technology

    2006-09-01

    complexes include the Rad51 paralogs family members such as (Rad51, Rad52, Rad54, Rad51B, Rad51C, Rad51D,Xrcc2and Xrcc3 ) and the breast cancer...DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 2002, 420, 287-293. 5. Xu ZY, Loignon M, Han FY, Panasci L, Aloyz R.. Xrcc3 ...Pharmacol Exp Ther. 2005, 314:495-505. 6. Xu ZY, Loignon M, Han FY, Panasci L, Aloyz R. Xrcc3 induces cisplatin resistance by stimulation of Rad51

  4. Characterization of BRCA2 Mutation in a Series of Functional Assays

    DTIC Science & Technology

    2005-05-01

    paraffin-embedded tissues of cattle and elk by PCR amplification of an IS6110 sequence specific for Mycobacterium tuberculosis complex organisms. J Vet...Sequence Variants 539 Thus, if one observes the variant n times, k of which are of causality of >1,000,000:1, showing the potential utility in conjunction...and 65, respec- of which potentially tests a different function of the pro- tively, whereas, for neutral variants, the corresponding tein. To

  5. The CASP8 rs3834129 polymorphism and breast cancer risk in BRCA1 mutation carriers.

    PubMed

    Catucci, Irene; Verderio, Paolo; Pizzamiglio, Sara; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Roversi, Gaia; Ripamonti, Carla B; Pasini, Barbara; Barile, Monica; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Varesco, Liliana; Martayan, Aline; Riboni, Mirko; Volorio, Sara; Radice, Paolo; Peterlongo, Paolo

    2011-02-01

    The rs3834129 polymorphism, in the promoter of CASP8 gene, has been recently reported as associated with breast cancer risk in the general population, with the minor allele del having a protective effect. Some of the genetic variants found associated with breast cancer risk were reported as risk modifiers in individuals with mutations in BRCA1 and BRCA2 genes. Here, we tested the effect of the rs3834129 del allele on breast cancer risk in BRCA mutation carriers. The rs3834129 was genotyped in a total of 1,207 Italian female BRCA mutation carriers. Of these, 740 carried a BRCA1 mutation and 467 a BRCA2 mutation. Overall, 699 were affected with breast cancer and 508 were unaffected. When considering class 1 (loss-of-function) BRCA mutations, hazard ratios estimated by weighted multivariable Cox regression model, for individuals with at least one copy of the del allele, were 1.46 (95% confidence interval (CI): 1.08-1.99) for BRCA1 and BRCA2 mutation carriers combined, 1.74 (95% CI: 1.24-2.46) for BRCA1 mutation carriers, and 1.09 (95% CI: 0.66-1.80) for BRCA2 mutation carriers. These results suggest that the minor allele del of rs3834129 is associated under a dominant model with increased breast cancer risk in carriers of BRCA1 mutations but not in carriers of BRCA2 mutations.

  6. Expression profile of BRCA1 and BRCA2 genes in premenopausal Mexican women with breast cancer: clinical and immunohistochemical correlates.

    PubMed

    Loredo-Pozos, Gloria; Chiquete, Erwin; Oceguera-Villanueva, Antonio; Panduro, Arturo; Siller-López, Fernando; Ramos-Márquez, Martha E

    2009-01-01

    Low BRCA1 gene expression is associated with increased invasiveness and influences the response of breast carcinoma (BC) to chemotherapeutics. However, expression of BRCA1 and BRCA2 genes has not been completely characterized in premenopausal BC. We analyzed the clinical and immunohistochemical correlates of BRCA1 and BRCA2 expression in young BC women. We studied 62 women (mean age 38.8 years) who developed BC before the age of 45 years. BRCA1 and BRCA2 mRNA expression was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and that of HER-2 and p53 proteins by immunohistochemistry. Body mass index (BMI) > or = 27 (52%) and a declared family history of BC (26%) were the main risk factors. Ductal infiltrative adenocarcinoma was found in 86% of the cases (tumor size >5 cm in 48%). Disease stages I-IV occurred in 2, 40, 55, and 3%, respectively (73% implicating lymph nodes). Women aged < or = 35 years (24%) had more family history of cervical cancer, stage III/IV disease, HER-2 positivity, and lower BRCA1 expression than older women (P < 0.05). BRCA1 and BRCA2 expression correlated in healthy, but not in tumor tissues (TT). Neither BRCA1 nor BRCA2 expression was associated with tumor histology, differentiation, nodal metastasis or p53 and HER-2 expression. After multivariate analysis, only disease stage explained BRCA1 mRNA levels in the lowest quartile. Premenopausal BC has aggressive clinical and molecular characteristics. Low BRCA1 mRNA expression is associated mainly with younger ages and advanced clinical stage of premenopausal BC. BRCA2 expression is not associated with disease severity in young BC women.

  7. Fanconi anemia complementation group D2 (FANCD2) functions independently of BRCA2- and RAD51-associated homologous recombination in response to DNA damage.

    PubMed

    Ohashi, Akihiro; Zdzienicka, Malgorzata Z; Chen, Junjie; Couch, Fergus J

    2005-04-15

    The BRCA2 breast cancer tumor suppressor is involved in the repair of double strand breaks and broken replication forks by homologous recombination through its interaction with DNA repair protein Rad51. Cells defective in BRCA2.FANCD1 are extremely sensitive to mitomycin C (MMC) similarly to cells deficient in any of the Fanconi anemia (FA) complementation group proteins (FANC). These observations suggest that the FA pathway and the BRCA2 and Rad51 repair pathway may be linked, although a functional connection between these pathways in DNA damage signaling remains to be determined. Here, we systematically investigated the interaction between these pathways. We show that in response to DNA damage, BRCA2-dependent Rad51 nuclear focus formation was normal in the absence of FANCD2 and that FANCD2 nuclear focus formation and mono-ubiquitination appeared normal in BRCA2-deficient cells. We report that the absence of BRCA2 substantially reduced homologous recombination repair of DNA breaks, whereas the absence of FANCD2 had little effect. Furthermore, we established that depletion of BRCA2 or Rad51 had a greater effect on cell survival in response to MMC than depletion of FANCD2 and that depletion of BRCA2 in FANCD2 mutant cells further sensitized these cells to MMC. Our results suggest that FANCD2 mediates double strand DNA break repair independently of Rad51-associated homologous recombination.

  8. High proportion of BRCA1/2 founder mutations in Hispanic breast/ovarian cancer families from Colombia.

    PubMed

    Torres, Diana; Rashid, Muhammad Usman; Gil, Fabian; Umana, Angela; Ramelli, Giancarlo; Robledo, Jose Fernando; Tawil, Mauricio; Torregrosa, Lilian; Briceno, Ignacio; Hamann, Ute

    2007-06-01

    In South America, a high proportion of the population is of Hispanic origin with an important representation in Colombia. Since nothing is known about the contribution of BRCA1 and BRCA2 germline mutations to hereditary breast/ovarian cancer in the Hispanic population from Colombia, we conducted the first study of 53 breast/ovarian cancer families from this country. Comprehensive BRCA mutation screening was performed using a range of techniques, including DHPLC, SSCP, and PTT, followed by DNA sequencing analysis. Thirteen deleterious germline mutations (24.5%) were identified in 53 families, comprising eight in BRCA1 and five in BRCA2. The two recurrent BRCA1 mutations, 3450 delCAAG and A1708E, accounted for 100% of all BRCA1 mutations identified in this cohort and the recurrent 3034 delACAA BRCA2 mutation for 40% of all BRCA2 mutations. Haplotype analyses suggested that each of these mutations has arisen from a common ancestor. The prevalence of BRCA1 or BRCA2 mutations was 50% in multiple case breast cancer families, and was 33% for the breast-ovarian cancer families. Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Colombia. The spectrum of mutations differed completely to that previously reported in Hispanic families of predominantly Mexican origin from Southern California [1] suggesting that specific genetic risk assessment strategies for the different Hispanic populations in South America and in the United States need to be developed.

  9. Brca2, Rad51 and Mre11: performing balancing acts on replication forks.

    PubMed

    Costanzo, Vincenzo

    2011-10-10

    Homologous recombination (HR) is required for faithful repair of double strand breaks (DSBs) and is believed to be important for DNA replication under stressful conditions in unicellular organisms. However, its role during DNA replication in high eukaryotes has always been elusive. In particular, due to the essential nature of its main players it has been difficult to dissect the direct role of HR in DNA replication. Recent studies revealed that some key HR factors such as Rad51 and BRCA2 play unexpected functions during DNA replication by protecting nascent DNA from Mre11 mediated degradation, which takes place at stalled replication forks. These novel functions appear to be essential to ensure smooth progression of DNA replication and to promote maintenance of genome stability.

  10. Substitution of Aspartate for glycine 1018 in the Type III procollagen (COL3AI) gene causes type IV Ehlers-Danlos Syndrome: The mutated allele is present in most blood leukocytes of the asymptomatic and mosaic mother

    SciTech Connect

    Kontusaari, S.; Tromp, G.; Kuivaniemi, H.; Prockop, D.J. ); Stolle, C. ); Pope, F.M.

    1992-09-01

    A proband with arterial ruptures and skin changes characteristic of the type IV variant of Ehlers-Danlos syndrome was found to have a single-base mutation in the type III procollagen gene, which converted the codon for glycine at amino position 1018 to a codon for aspartate. (Amino acid positions are numbered by the standard convention in which the first glycine of the triple-helical domain of an [alpha] chain is number 1. The numbers of positions in the [alpha]1(III) chains can be converted to positions in the human pro[alpha](III) chain by adding 167.). Nucleotide sequencing of overlapping PCR products in which the two alleles were distinguished demonstrated that the mutation of glycine 1018 was the only mutation that changed the primary structure of type III procollagen. The glycine substitution markedly decreased the amount of type III procollagen secreted into the medium by cultured skin fibroblasts from the proband. It is surprising that the same mutation was found in about 94% of the peripheral blood leukocytes from the proband's asymptomatic 72-year-old mother. Other tissues from the mother contained the mutated allele; it was present in 0%-100% of different samples of hair cells and in about 40% of cells from the oral epithelium. Therefore, the mother was a mosaic for the mutation. Since the mutated allele was present in cells derived from all three germ layers, the results indicated that the mutation arose by the late blastocyst stage of development. The results also indicate that assays of blood leukocytes do not always reveal mosaicism or predict phenotypic involvement of tissues, such as blood vessels, that are derived from the same embryonic cells as are leukocytes. 66 refs., 6 figs., 1 tab.

  11. BRCA somatic and germline mutation detection in paraffin embedded ovarian cancers by next-generation sequencing

    PubMed Central

    Mafficini, Andrea; Simbolo, Michele; Parisi, Alice; Rusev, Borislav; Luchini, Claudio; Cataldo, Ivana; Piazzola, Elena; Sperandio, Nicola; Turri, Giona; Franchi, Massimo; Tortora, Giampaolo; Bovo, Chiara; Lawlor, Rita T.; Scarpa, Aldo

    2016-01-01

    BRCA mutated ovarian cancers respond better to platinum-based therapy and to the recently approved PARP-inhibitors. There is the need for efficient and timely methods to detect both somatic and germline mutations using formalin-fixed paraffin-embedded (FFPE) tissues and commercially available technology. We used a commercial kit exploring all exons and 50bp exon-intron junctions of BRCA1 and BRCA2 genes, and semiconductor next-generation sequencing (NGS) on DNA from 47 FFPE samples of high-grade serous ovarian cancers. Pathogenic mutations were found in 13/47 (28%) cancers: eight in BRCA1 and five in BRCA2. All BRCA1 and two BRCA2 mutations were germline; three BRCA2 mutations were somatic. All mutations were confirmed by Sanger sequencing. To evaluate the performance of the NGS panel, we assessed its capability to detect the 6,953 variants described for BRCA1 and BRCA2 in ClinVar and COSMIC databases using callability analysis. 6,059 (87.1%) variants were identified automatically by the software; 829 (12.0%) required visual verification. The remaining 65 (0.9%) variants were uncallable, and would require 15 Sanger reactions to be resolved. Thus, the sensitivity of the NGS-panel was 99.1%. In conclusion, NGS performed with a commercial kit is highly efficient for detection of germline and somatic mutations in BRCA genes using routine FFPE tissue. PMID:26745875

  12. BRCA somatic and germline mutation detection in paraffin embedded ovarian cancers by next-generation sequencing.

    PubMed

    Mafficini, Andrea; Simbolo, Michele; Parisi, Alice; Rusev, Borislav; Luchini, Claudio; Cataldo, Ivana; Piazzola, Elena; Sperandio, Nicola; Turri, Giona; Franchi, Massimo; Tortora, Giampaolo; Bovo, Chiara; Lawlor, Rita T; Scarpa, Aldo

    2016-01-12

    BRCA mutated ovarian cancers respond better to platinum-based therapy and to the recently approved PARP-inhibitors. There is the need for efficient and timely methods to detect both somatic and germline mutations using formalin-fixed paraffin-embedded (FFPE) tissues and commercially available technology. We used a commercial kit exploring all exons and 50bp exon-intron junctions of BRCA1 and BRCA2 genes, and semiconductor next-generation sequencing (NGS) on DNA from 47 FFPE samples of high-grade serous ovarian cancers. Pathogenic mutations were found in 13/47 (28%) cancers: eight in BRCA1 and five in BRCA2. All BRCA1 and two BRCA2 mutations were germline; three BRCA2 mutations were somatic. All mutations were confirmed by Sanger sequencing. To evaluate the performance of the NGS panel, we assessed its capability to detect the 6,953 variants described for BRCA1 and BRCA2 in ClinVar and COSMIC databases using callability analysis. 6,059 (87.1%) variants were identified automatically by the software; 829 (12.0%) required visual verification. The remaining 65 (0.9%) variants were uncallable, and would require 15 Sanger reactions to be resolved. Thus, the sensitivity of the NGS-panel was 99.1%. In conclusion, NGS performed with a commercial kit is highly efficient for detection of germline and somatic mutations in BRCA genes using routine FFPE tissue.

  13. Next-generation sequencing meets genetic diagnostics: development of a comprehensive workflow for the analysis of BRCA1 and BRCA2 genes.

    PubMed

    Feliubadaló, Lídia; Lopez-Doriga, Adriana; Castellsagué, Ester; del Valle, Jesús; Menéndez, Mireia; Tornero, Eva; Montes, Eva; Cuesta, Raquel; Gómez, Carolina; Campos, Olga; Pineda, Marta; González, Sara; Moreno, Victor; Brunet, Joan; Blanco, Ignacio; Serra, Eduard; Capellá, Gabriel; Lázaro, Conxi

    2013-08-01

    Next-generation sequencing (NGS) is changing genetic diagnosis due to its huge sequencing capacity and cost-effectiveness. The aim of this study was to develop an NGS-based workflow for routine diagnostics for hereditary breast and ovarian cancer syndrome (HBOCS), to improve genetic testing for BRCA1 and BRCA2. A NGS-based workflow was designed using BRCA MASTR kit amplicon libraries followed by GS Junior pyrosequencing. Data analysis combined Variant Identification Pipeline freely available software and ad hoc R scripts, including a cascade of filters to generate coverage and variant calling reports. A BRCA homopolymer assay was performed in parallel. A research scheme was designed in two parts. A Training Set of 28 DNA samples containing 23 unique pathogenic mutations and 213 other variants (33 unique) was used. The workflow was validated in a set of 14 samples from HBOCS families in parallel with the current diagnostic workflow (Validation Set). The NGS-based workflow developed permitted the identification of all pathogenic mutations and genetic variants, including those located in or close to homopolymers. The use of NGS for detecting copy-number alterations was also investigated. The workflow meets the sensitivity and specificity requirements for the genetic diagnosis of HBOCS and improves on the cost-effectiveness of current approaches.

  14. Development and Validation of a Next-Generation Sequencing Assay for BRCA1 and BRCA2 Variants for the Clinical Laboratory

    PubMed Central

    Strom, Charles M.; Rivera, Steven; Elzinga, Christopher; Angeloni, Taraneh; Rosenthal, Sun Hee; Goos-Root, Dana; Siaw, Martin; Platt, Jamie; Braastadt, Cory; Cheng, Linda; Ross, David; Sun, Weimin

    2015-01-01

    The objective of this study was to design and validate a next-generation sequencing assay (NGS) to detect BRCA1 and BRCA2 mutations. We developed an assay using random shearing of genomic DNA followed by RNA bait tile hybridization and NGS sequencing on both the Illumina MiSeq and Ion Personal Gene Machine (PGM). We determined that the MiSeq Reporter software supplied with the instrument could not detect deletions greater than 9 base pairs. Therefore, we developed an alternative alignment and variant calling software, Quest Sequencing Analysis Pipeline (QSAP), that was capable of detecting large deletions and insertions. In validation studies, we used DNA from 27 stem cell lines, all with known deleterious BRCA1 or BRCA2 mutations, and DNA from 67 consented control individuals who had a total of 352 benign variants. Both the MiSeq/QSAP combination and PGM/Torrent Suite combination had 100% sensitivity for the 379 known variants in the validation series. However, the PGM/Torrent Suite combination had a lower intra- and inter-assay precision of 96.2% and 96.7%, respectively when compared to the MiSeq/QSAP combination of 100% and 99.4%, respectively. All PGM/Torrent Suite inconsistencies were false-positive variant assignments. We began commercial testing using both platforms and in the first 521 clinical samples MiSeq/QSAP had 100% sensitivity for BRCA1/2 variants, including a 64-bp deletion and a 10-bp insertion not identified by PGM/Torrent Suite, which also suffered from a high false-positive rate. Neither the MiSeq nor PGM platform with their supplied alignment and variant calling software are appropriate for a clinical laboratory BRCA sequencing test. We have developed an NGS BRCA1/2 sequencing assay, MiSeq/QSAP, with 100% analytic sensitivity and specificity in the validation set consisting of 379 variants. The MiSeq/QSAP combination has sufficient performance for use in a clinical laboratory. PMID:26295337

  15. Functional Analysis of Variants of Unknown Significance in BRCA1 and BRCA2 Using Complementation of a Synthetic Lethal Interaction with PARP Inhibition

    DTIC Science & Technology

    2014-12-01

    Award Number: W81XWH-12-1-0569 TITLE: Functional Analysis of Variants of Unknown Significance in BRCA1 and BRCA2 Using Complementation of a...synergistic decrease in cell survival in cells with loss of function of either BRCA1 or BRCA2 and loss or inhibition of Parp1 activity15,17. SLI has...Develop a robust assay by which individual VUSs can be tested for their effect on BRCA1 /2 function by expressing a BRCA1 or BRCA2 gene (cDNA) carrying the

  16. Assessing the RNA effect of 26 DNA variants in the BRCA1 and BRCA2 genes.

    PubMed

    Menéndez, Mireia; Castellsagué, Joan; Mirete, Marc; Pros, Eva; Feliubadaló, Lídia; Osorio, Ana; Calaf, Mónica; Tornero, Eva; del Valle, Jesús; Fernández-Rodríguez, Juana; Quiles, Francisco; Salinas, Mónica; Velasco, Angela; Teulé, Alex; Brunet, Joan; Blanco, Ignacio; Capellá, Gabriel; Lázaro, Conxi

    2012-04-01

    Comprehensive genetic testing of the breast cancer susceptibility genes BRCA1 and BRCA2 identified approximately 16% of variants of unknown significance (VUS), a significant proportion of which could affect the correct splicing of the genes. Our aim is to establish a workflow for classifying VUS in these complex genes, the first stage of which is splicing analysis. We used a combined approach consisting of five in silico splicing prediction programs and RT-PCR analysis for a set of 26 variants not previously studied at the mRNA level and six variants that had already been studied, four of which were used as positive controls as they were found to affect the splicing of these genes and the other two were used as negative controls. We identified a splicing defect in 8 of the 26 newly studied variants and ruled out splicing alteration in the remaining 18 variants. The results for the four positive and the two negative control variants were consistent with results presented in the literature. Our results strongly suggest that the combination of RNA analysis and in silico programs is an important step towards the classification of VUS. The results revealed a very high correlation between experimental data and in silico programs when using tools for predicting acceptor/donor sites but a lower correlation in the case of tools for identifying ESE elements.

  17. Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer.

    PubMed Central

    Beckmann, M. W.; Picard, F.; An, H. X.; van Roeyen, C. R.; Dominik, S. I.; Mosny, D. S.; Schnürch, H. G.; Bender, H. G.; Niederacher, D.

    1996-01-01

    The development of familial and sporadic breast cancer is based on genetic alterations of tumour-suppressor genes, for which loss of heterozygosity (LOH) is one mechanism of gene inactivation. To investigate LOH of BRCA1 (17q21) and BRCA2 (13-q12-13) in sporadic breast cancer, polymerase chain reaction (PCR)-based fluorescent DNA technology for detection of microsatellite polymorphisms was applied. A total of 137 breast cancer and 15 benign breast specimens with matched normal tissue were examined. Fluorescent-labelled PCR products were analysed in an automated DNA sequencer (ALFTM Pharmacia). Losses at both loci were correlated with different histological types, age, tumour size, lymph node status, grading and steroid hormone receptor expression, [SHR: oestrogen receptor (ER), progesterone receptor (PgR)]. For BRCA1 (D17S855, THRA1, D17S579) losses could be detected in invasive ductal carcinoma (IDC; n = 108) in 32-38%, invasive lobular carcinoma (ILC; n = 19) in 21-42% depending on the marker applied, but not in benign breast tumours (n = 15). Losses of BRCA1 markers correlated with larger tumour size, higher grade, and PgR expression. For BRCA2 (D13S260, D13S267, D13S171) losses could be detected in 108 IDCs in 30-38%, in 19 ILCs in 17-39% depending on the marker applied, but not in benign breast tumours. Losses of BRCA2 markers correlated only with higher grade. Microsatellite analyses combined with detection of fluorescent-labelled PCR products by an automated laser DNA sequencer can be used for routine determination of LOH. In sporadic breast cancer, LOH of BRCA1 of BRCA2 does not add decisive prognostic value as stated for familial breast cancer. Images Figure 1 PMID:8630282

  18. Exploiting the Achilles heel of cancer: the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in BRCA2-defective cancer.

    PubMed

    Kyle, S; Thomas, H D; Mitchell, J; Curtin, N J

    2008-10-01

    Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates DNA single-strand break-base excision repair to maintain genomic stability. Inhibition or loss of PARP activity leads to a recombinogenic phenotype characterized by increased sister chromatid exchange. Deficiency in homologous recombination (HR) owing to loss of BRCA1 or BRCA2 is associated with hereditary cancers of the breast, ovary, pancreas and prostate. We investigated the therapeutic potential of PARP inhibitors in HR and BRCA2-defective cells. We exposed cells defective in the HR component XRCC3 (irs1SF) and BRCA2 (V-C8) and their parental (AA8, V79) or deficiency corrected (CXR3, V-C8+B2) cells to the PARP inhibitors NU1025 and AG14361. Mice bearing BRCA2-deficient and BRCA2-proficient tumours were treated with AG14361. All HR-defective cells were hypersensitive to normally non-cytotoxic concentrations of PARP inhibitors. Cells lacking BRCA2 were 20 times more sensitive to PARP inhibitor-induced cytotoxicity. Three out of five BRCA2-defective xenografts responded to the potent PARP inhibitor, AG14361, and one tumour regressed completely, compared with non-responses in the BRCA2-proficient tumours treated with AG14361 or any mice treated with vehicle control. Untreated PARP-1(-/-) mouse embryo fibroblasts (MEFs) accumulated more DNA double-strand breaks than did PARP-1(+/+) MEFs. We believe the underlying cytotoxic mechanism is due to PARP inhibitor-mediated suppression of repair of DNA single-strand breaks, which are converted to DNA double-strand breaks at replication. These replication-associated double-strand breaks, which are normally repaired by HR, become cytotoxic in cells defective in HR. Using a DNA repair inhibitor alone to selectively kill a tumour represents an exciting new concept in cancer therapy.

  19. Detection of false positive mutations in BRCA gene by next generation sequencing.

    PubMed

    Suryavanshi, Moushumi; Kumar, Dushyant; Panigrahi, Manoj Kumar; Chowdhary, Meenakshi; Mehta, Anurag

    2016-11-15

    BRCA1 and BRCA2 genes are implicated in 20-25% of hereditary breast and ovarian cancers. New age sequencing platforms have revolutionized massively parallel sequencing in clinical practice by providing cost effective, rapid, and sensitive sequencing. This study critically evaluates the false positives in multiplex panels and suggests the need for careful analysis. We employed multiplex PCR based BRCA1 and BRCA2 community Panel with ion torrent PGM machine for evaluation of these mutations. Out of all 41samples analyzed for BRCA1 and BRCA2 five were found with 950_951 insA(Asn319fs) at Chr13:32906565 position and one sample with 1032_1033 insA(Asn346fs) at Chr13:32906647, both being frame-shift mutations in BRCA2 gene. 950_951 insA(Asn319fs) mutation is reported as pathogenic allele in NCBI dbSNP. On examination of IGV for all these samples, it was seen that both mutations had 'A' nucleotide insertion at 950, and 1032 position in exon 10 of BRCA2 gene. Sanger Sequencing did not confirm these insertions. Next-generation sequencing shows great promise by allowing rapid mutational analysis of multiple genes in human cancer but our results indicate the need for careful sequence analysis to avoid false positive results.

  20. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes.

    PubMed

    Easton, Douglas F; Deffenbaugh, Amie M; Pruss, Dmitry; Frye, Cynthia; Wenstrup, Richard J; Allen-Brady, Kristina; Tavtigian, Sean V; Monteiro, Alvaro N A; Iversen, Edwin S; Couch, Fergus J; Goldgar, David E

    2007-11-01

    Mutation screening of the breast and ovarian cancer-predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare nontruncating sequence variants in these genes is problematic, because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Using data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433 sequence variants of unknown significance (VUSs) in the BRCA genes. Three independent measures were employed in the assessment: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees. For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an "average" deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. A total of 133 VUSs had odds of at least 100 : 1 in favor of neutrality with respect to risk, whereas 43 had odds of at least 20 : 1 in favor of being deleterious. VUSs with evidence in favor of causality were those that were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. In addition to their utility for improved genetics counseling of patients and their families, the global assessment reported here will be invaluable for validation of functional assays, structural models, and in silico analyses.

  1. Breast and ovarian cancer risk evaluation in families with a disease-causing mutation in BRCA1/2.

    PubMed

    Beristain, Elena; Ibáñez, Berta; Vergara, Itziar; Martínez-Bouzas, Cristina; Guerra, Isabel; Tejada, Maria Isabel

    2010-06-01

    Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, and their identification allows genetic testing of at-risk relatives. However, estimates of these risks illustrate controversies, depending on the published series. The penetrance, the earlier onset of the disease and the effect of mutations on the risk of developing breast and ovarian cancer were evaluated in 344 females belonging to 34 families from the Basque Country in Spain, in which BRCA1 or BRCA2 mutations were transmitted. Kaplan-Meier survival curves were used to derive cumulative probability curves for breast and ovarian cancer by mutation status, birth cohort and mutation position, and significance of the differences was assessed using the log-rank test. The estimated probability for breast cancer by age 70 is about 64% in BRCA1 and 69% in BRCA2, whereas the probability of developing ovarian cancer is about 37% and 25% for BRCA1 and BRCA2, respectively. There is a marginally significant higher risk of developing ovarian cancer in BRCA1 families than in BRCA2 families. The effect of birth cohort on breast cancer cumulative incidence presents an increased risk for females born after 1966 and a decreased risk for those born before 1940. There is no association between mutation position and breast cancer; however, ovarian cancer is associated to BRCA1, presenting exon 11 as an ovarian cluster. These results are important for the breast and ovarian cancer diagnosis and prevention in at-risk families.

  2. Asymptomatic and late-onset ornithine transcarbamylase deficiency caused by a A208T mutation: Clinical, biochemical and DNA analyses in a four-generation family

    SciTech Connect

    Ausems, M.G.E.M.; Bakker, E.; Kneppers, A.L.J.

    1997-01-20

    We describe a 4-generation family in which a previously healthy 10-year-old boy died of late-onset ornithine transcarbamylase (OTC) deficiency. Pedigree analysis and allopurinol loading tests in female relatives were not informative. A missense mutation (A208T) in the OTC gene was detected in the deceased patient and in several clinically healthy male and female relatives, the oldest male being 97 years old. OTC deficiency was established in autopsy liver tissue of the propositus and liver biopsy samples of his sister, mother, and a maternal uncle. The males had 4% and 6% residual activity, respectively, the females 58% and 67%, respectively. The observed relation between the mutation and the decreased OTC activity in liver tissue of these subjects suggests that the mutation is a deleterious one. Late-onset, {open_quotes}mild{close_quotes} OTC deficiency can have a fatal or a favorable outcome. The disease can segregate undetected in families. 16 refs., 1 fig., 1 tab.

  3. BRCA2 is needed for both repair and cell cycle arrest in mammalian cells exposed to S23906, an anticancer monofunctional DNA binder

    PubMed Central

    Rocca, Céline J; Soares, Daniele G; Bouzid, Hana; Henriques, João A P; Larsen, Annette K; Escargueil, Alexandre E

    2015-01-01

    Repair of DNA-targeted anticancer agents is an active area of investigation of both fundamental and clinical interest. However, most studies have focused on a small number of compounds limiting our understanding of both DNA repair and the DNA damage response. S23906 is an acronycine derivative that shows strong activity toward solid tumors in experimental models. S23906 forms bulky monofunctional DNA adducts in the minor groove which leads to destabilization of the double-stranded helix. We now report that S23906 induces formation of DNA double strand breaks that are processed through homologous recombination (HR) but not Non-Homologous End-Joining (NHEJ) repair. Interestingly, S23906 exposure was accompanied by a higher sensitivity of BRCA2-deficient cells compared to other HR deficient cell lines and by an S-phase accumulation in wild-type (wt), but not in BRCA2-deficient cells. Recently, we have shown that S23906-induced S phase arrest was mediated by the checkpoint kinase Chk1. However, its activated phosphorylated form is equally induced by S23906 in wt and BRCA2-deficient cells, likely indicating a role for BRCA2 downstream of Chk1. Accordingly, override of the S phase arrest by either 7-hydroxystaurosporine (UCN-01) or AZD7762 potentiates the cytotoxic activity of S23906 in wt, but not in BRCA2-deficient cells. Together, our findings suggest that the pronounced sensitivity of BRCA2-deficient cells to S23906 is due to both a defective S-phase arrest and the absence of HR repair. Tumors with deficiencies for proteins involved in HR, and BRCA2 in particular, may thus show increased sensitivity to S23906, thereby providing a rationale for patient selection in clinical trials. PMID:25945522

  4. Asymptomatic HIV infection

    MedlinePlus

    ... infection URL of this page: //medlineplus.gov/ency/article/000682.htm Asymptomatic HIV infection To use the sharing features on this page, please enable JavaScript. Asymptomatic HIV infection is a phase of HIV/AIDS during which there are no symptoms of HIV ...

  5. FANCD2, FANCJ and BRCA2 cooperate to promote replication fork recovery independently of the Fanconi Anemia core complex.

    PubMed

    Raghunandan, Maya; Chaudhury, Indrajit; Kelich, Stephanie L; Hanenberg, Helmut; Sobeck, Alexandra

    2015-01-01

    Fanconi Anemia (FA) is an inherited multi-gene cancer predisposition syndrome that is characterized on the cellular level by a hypersensitivity to DNA interstrand crosslinks (ICLs). To repair these lesions, the FA pathway proteins are thought to act in a linear hierarchy: Following ICL detection, an upstream FA core complex monoubiquitinates the central FA pathway members FANCD2 and FANCI, followed by their recruitment to chromatin. Chromatin-bound monoubiquitinated FANCD2 and FANCI subsequently coordinate DNA repair factors including the downstream FA pathway members FANCJ and FANCD1/BRCA2 to repair the DNA ICL. Importantly, we recently showed that FANCD2 has additional independent roles: it binds chromatin and acts in concert with the BLM helicase complex to promote the restart of aphidicolin (APH)-stalled replication forks, while suppressing the firing of new replication origins. Here, we show that FANCD2 fulfills these roles independently of the FA core complex-mediated monoubiquitination step. Following APH treatment, nonubiquitinated FANCD2 accumulates on chromatin, recruits the BLM complex, and promotes robust replication fork recovery regardless of the absence or presence of a functional FA core complex. In contrast, the downstream FA pathway members FANCJ and BRCA2 share FANCD2's role in replication fork restart and the suppression of new origin firing. Our results support a non-linear FA pathway model at stalled replication forks, where the nonubiquitinated FANCD2 isoform - in concert with FANCJ and BRCA2 - fulfills a specific function in promoting efficient replication fork recovery independently of the FA core complex.

  6. Prostate Cancer in a Patient with a Family History of BRCA Mutation: a Case Report and Literature Review

    PubMed Central

    2017-01-01

    One of the most significant risk factors for prostate cancer (PC) is a family history of the disease, with germ-line mutations in the breast cancer predisposition gene (BRCA) 2 conferring the highest risk. We here report a 56-year-old man presented with painful gait disturbance and diagnosed PC with multiple disseminated bone metastases. The patient had a strong family history of breast cancer with his 2 nieces affected. Furthermore, his aunts and uncles from both sides were diagnosed with stomach, ovarian, and colorectal cancers. His genomic sequencing analysis of the BRCA genes revealed the same BRCA2 deleterious mutation that his breast cancer-affected nieces carried. Previous studies have suggested that BRCA2-mutated PC is associated with a more aggressive phenotype and poor prognosis. Our experience in the present case also indicated the urgent needs for novel treatment modality and PC screening in this high-risk group of patients. PMID:28049253

  7. Prostate Cancer in a Patient with a Family History of BRCA Mutation: a Case Report and Literature Review.

    PubMed

    Song, Won Hoon; Kim, Sung Han; Joung, Jae Young; Park, Weon Seo; Seo, Ho Kyung; Chung, Jinsoo; Lee, Kang Hyun

    2017-02-01

    One of the most significant risk factors for prostate cancer (PC) is a family history of the disease, with germ-line mutations in the breast cancer predisposition gene (BRCA) 2 conferring the highest risk. We here report a 56-year-old man presented with painful gait disturbance and diagnosed PC with multiple disseminated bone metastases. The patient had a strong family history of breast cancer with his 2 nieces affected. Furthermore, his aunts and uncles from both sides were diagnosed with stomach, ovarian, and colorectal cancers. His genomic sequencing analysis of the BRCA genes revealed the same BRCA2 deleterious mutation that his breast cancer-affected nieces carried. Previous studies have suggested that BRCA2-mutated PC is associated with a more aggressive phenotype and poor prognosis. Our experience in the present case also indicated the urgent needs for novel treatment modality and PC screening in this high-risk group of patients.

  8. Moonlighting at replication forks - a new life for homologous recombination proteins BRCA1, BRCA2 and RAD51.

    PubMed

    Kolinjivadi, Arun Mouli; Sannino, Vincenzo; de Antoni, Anna; Técher, Hervé; Baldi, Giorgio; Costanzo, Vincenzo

    2017-01-12

    Coordination between DNA replication and DNA repair ensures maintenance of genome integrity, which is lost in cancer cells. Emerging evidence has linked homologous recombination (HR) proteins RAD51, BRCA1 and BRCA2 to the stability of nascent DNA. This function appears to be distinct from double-strand break (DSB) repair and is in part due to the prevention of MRE11-mediated degradation of nascent DNA at stalled forks. The role of RAD51 in fork protection resembles the activity described for its prokaryotic orthologue RecA, which prevents nuclease-mediated degradation of DNA and promotes replication fork restart in cells challenged by DNA-damaging agents. Here, we examine the mechanistic aspects of HR-mediated fork protection, addressing the crosstalk between HR and replication proteins.

  9. A mutational signature in gastric cancer suggests therapeutic strategies

    DOE PAGES

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Siu, Hoi Cheong; ...

    2015-10-29

    Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer andmore » demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Furthermore, our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors.« less

  10. A mutational signature in gastric cancer suggests therapeutic strategies

    SciTech Connect

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Siu, Hoi Cheong; Leung, Suet Yi; Stratton, Michael R.

    2015-10-29

    Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Furthermore, our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors.

  11. A mutational signature in gastric cancer suggests therapeutic strategies

    PubMed Central

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Siu, Hoi Cheong; Leung, Suet Yi; Stratton, Michael R

    2015-01-01

    Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors. PMID:26511885

  12. Characterization of BRCA1/2 mutations in patients with family history of breast cancer in Armenia

    PubMed Central

    Atshemyan, Sofi; Chavushyan, Andranik; Berberian, Nerses; Sahakyan, Arthur; Zakharyan, Roksana; Arakelyan, Arsen

    2017-01-01

    Background. Breast cancer is one of the most common cancers in women worldwide. The germline mutations of the BRCA1 and BRCA2 genes are the most significant and well characterized genetic risk factors for hereditary breast cancer. Intensive research in the last decades has demonstrated that the incidence of mutations varies widely among different populations. In this study we attempted to perform a pilot study for identification and characterization of mutations in BRCA1 and BRCA2 genes among Armenian patients with family history of breast cancer and their healthy relatives.  Methods. We performed targeted exome sequencing for BRCA1 and BRCA2 genes in 6 patients and their healthy relatives. After alignment of short reads to the reference genome, germline single nucleotide variation and indel discovery was performed using GATK software. Functional implications of identified variants were assessed using ENSEMBL Variant Effect Predictor tool.  Results. In total, 39 single nucleotide variations and 4 indels were identified, from which 15 SNPs and 3 indels were novel. No known pathogenic mutations were identified, but 2 SNPs causing missense amino acid mutations had significantly increased frequencies in the study group compared to the 1000 Genome populations.  Conclusions. Our results demonstrate the importance of screening of BRCA1 and BRCA2 gene variants in the Armenian population in order to identity specifics of mutation spectrum and frequencies and enable accurate risk assessment of hereditary breast cancers. PMID:28357044

  13. Suppression of BRCA2 by Mutant Mitochondrial DNA in Prostate Cancer

    DTIC Science & Technology

    2011-05-01

    Nonidet P - 40 , 2 mmol/L phenylmethylsulfonyl fluoride, 10 g/mL aprotinin, 10 g/mL leupeptin, 10 mmol/L sodium fluoride, 1 mmol/L sodium orthovanadate, and...specimens were pulverized and homogenized in lysis buffer containing 0.1% SDS, 1% Non- idet P - 40 , 50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 200...Analyze the correlation between type/number of mtDNA mutations and clinical stage (Months 10-11) We extracted total DNA from 6 BPH and 40 PCA frozen

  14. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis.

    PubMed

    Bu, Rong; Siraj, Abdul K; Al-Obaisi, Khadija A S; Beg, Shaham; Al Hazmi, Mohsen; Ajarim, Dahish; Tulbah, Asma; Al-Dayel, Fouad; Al-Kuraya, Khawla S

    2016-09-01

    Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy.

  15. Tumour morphology predicts PALB2 germline mutation status

    PubMed Central

    Teo, Z L; Provenzano, E; Dite, G S; Park, D J; Apicella, C; Sawyer, S D; James, P A; Mitchell, G; Trainer, A H; Lindeman, G J; Shackleton, K; Cicciarelli, L; Buys, S S; Andrulis, I L; Mulligan, A M; Glendon, G; John, E M; Terry, M B; Daly, M; Odefrey, F A; Nguyen-Dumont, T; Giles, G G; Dowty, J G; Winship, I; Goldgar, D E; Hopper, J L; Southey, M C

    2013-01-01

    Background: Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status. Methods: Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations. Results: Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0–64.6; P=5 × 10−7). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers. Conclusion: This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2. PMID:23787919

  16. Prevalence and clinical significance of BRCA1/2 germline and somatic mutations in Taiwanese patients with ovarian cancer.

    PubMed

    Chao, Angel; Chang, Ting-Chang; Lapke, Nina; Jung, Shih-Ming; Chi, Peter; Chen, Chien-Hung; Yang, Lan-Yan; Lin, Cheng-Tao; Huang, Huei-Jean; Chou, Hung-Hsueh; Liou, Jui-Der; Chen, Shu-Jen; Wang, Tzu-Hao; Lai, Chyong-Huey

    2016-12-20

    Germline and somatic BRCA1/2 mutations define a subset of patients with ovarian cancer who may benefit from treatment with poly (ADP-ribose) polymerase inhibitors. Unfortunately, data on the frequency of BRCA1/2 germline mutations in Taiwanese patients with ovarian cancer are scarce, with the prevalence of somatic mutations being unknown. We aim to investigate the occurrence of BRCA1/2 mutations in 99 Taiwanese patients with ovarian cancer which included serous (n = 46), endometrioid (n = 24), and clear cell (n = 29) carcinomas. BRCA1/2 mutations were identified using next-generation sequencing of formalin-fixed paraffin-embedded tumor samples. Pathogenic variants (BRCA1: n = 7; BRCA2: n = 6) were detected in 12.1% (12/99) of the study patients. Somatic and germline BRCA1/2 mutation rates in serous ovarian cancer are 4/46 (8.7%) and 8/46 (17%), respectively. All of the pathogenic BRCA1/2 mutations were identified in serous carcinoma samples (12/46; 26.1%). One-third (4/12) of the deleterious BRCA1/2 mutations occurred in tumor tissues only (somatic mutations). All of them coexisted with loss of heterozygosity, resulting in biallelic BRCA inactivation. Five novel pathogenic mutations were identified, including four somatic variants (BRCA1 p.S242fs, BRCA1 p.F989fs, BRCA1 p.G1738fs, and BRCA2 p.D1451fs) and a germline variant (BRCA2 p.E260fs). We also detected additional six novel mutations (three in BRCA1 and three in BRCA2) with pathogenic potentials. We conclude that BRCA1/2 mutations are common in Taiwanese patients with serous ovarian carcinoma and similar to mutation rates in other ethnic groups. The analysis of BRCA1/2 somatic mutations is crucial for guiding therapeutic decisions in ovarian cancer.

  17. Characteristics of BRCA1/2 Mutation-Positive Breast Cancers in Korea: A Comparison Study Based on Multicenter Data and the Korean Breast Cancer Registry

    PubMed Central

    Yu, Jong-Han; Son, Byung Ho; Kim, Sung-Won; Park, Sue K.; Lee, Min Hyuk; Kim, Lee Su; Noh, Woo-Chul; Kim, Eun-Kyu; Yoon, Dae Sung; Lee, Jeeyeon; Jung, Jin Hyang; Jung, Sang Seol; Gong, Gyungyup; Ahn, Sei-Hyun

    2014-01-01

    Purpose Mutations in BRCA genes are the main cause of hereditary breast cancer in Korea. The aim of this study was to investigate the characteristics of breast cancers involving BRCA1 (BRCA1 group) and BRCA2 (BRCA2 group) mutations. Methods We retrospectively reviewed the medical records of patients with BRCA1 (BRCA1 group) or BRCA2 (BRCA2 group) mutation positive breast cancer from multiple centers and compared the data to that of the Korean Breast Cancer Society registry (registry group). Results The patients of the BRCA1 group were diagnosed at a younger age (median age, 37 years) and had tumors of higher histological (61.3% with histological grade 3) and nuclear (37.5% with nuclear grade 3) grade than those of the registry group. In addition, the frequency of ductal carcinoma in situ in the BRCA1 group was lower (3.7%) than in the registry group, and the BRCA1 group were more likely to be triple-negative breast cancer (61.3%). Patients in the BRCA2 group were also younger at diagnosis (mean age, 41 years) and were more likely to have involvement of the axillary node than the registry group (45.5% vs. 33.5%, p=0.002). The BRCA1 and BRCA2 groups did not show a correlation between tumor size and axillary node involvement. Conclusion We report the characteristics of BRCA mutation positive breast cancer patients in the Korean population through multicenter data and nation-wide breast cancer registry study. However, BRCA-mutated breast cancers appear highly complex, and further research on their molecular basis is needed in Korea. PMID:25013433

  18. The spectrum of BRCA1 and BRCA2 alleles in Latin America and the Caribbean: a clinical perspective.

    PubMed

    Dutil, Julie; Golubeva, Volha A; Pacheco-Torres, Alba L; Diaz-Zabala, Hector J; Matta, Jaime L; Monteiro, Alvaro N

    2015-12-01

    Hereditary cancer predisposition gene testing allows the identification of individuals at high risk of cancer that may benefit from increased surveillance, chemoprevention, and prophylactic surgery. In order to implement clinical genetic strategies adapted to each population's needs and intrinsic genetic characteristic, this review aims to present the current status of knowledge about the spectrum of BRCA pathogenic variants in Latin American populations. We have conducted a comprehensive review of 33 studies published between 1994 and 2015 reporting the prevalence and/or spectrum of BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) variants. The combined sample size for these studies consisted of 4835 individuals from 13 countries in Latin America and the Caribbean, as well as in Hispanics in the United States. A total of 167 unique pathogenic variants have been reported in the existing literature. In unselected breast cancer cases, the prevalence ranged from 1.2 to 27.1%. Some countries presented a few recurrent pathogenic variants, while others were characterized by diverse, non-recurrent variants. The proportion of BRCA pathogenic variants shared between Hispanics in the United States and Latin American populations was estimated at 10.4%. Within Latin America and the Caribbean, 8.2% of the BRCA variants reported were present in more than one country. Countries with high prevalence of BRCA pathogenic variants may benefit from more aggressive testing strategies, while testing of recurrent variant panels might present a cost-effective solution for improving genetic testing in some, but not all, countries.

  19. RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination.

    PubMed

    Lok, B H; Carley, A C; Tchang, B; Powell, S N

    2013-07-25

    Synthetic lethality is an approach to study selective cell killing based on genotype. Previous work in our laboratory has shown that loss of RAD52 is synthetically lethal with BRCA2 deficiency, while exhibiting no impact on cell growth and viability in BRCA2-proficient cells. We now show that this same synthetically lethal relationship is evident in cells with deficiencies in BRCA1 or PALB2, which implicates BRCA1, PALB2 and BRCA2 in an epistatic relationship with one another. When RAD52 was depleted in BRCA1- or PALB2-deficient cells, a severe reduction in plating efficiency was observed, with many abortive attempts at cell division apparent in the double-depleted background. In contrast, when RAD52 was depleted in a BRCA1- or PALB2-wildtype background, a negligible decrease in colony survival was observed. The frequency of ionizing radiation-induced RAD51 foci formation and double-strand break-induced homologous recombination (HR) was decreased by 3- and 10-fold, respectively, when RAD52 was knocked down in BRCA1- or PALB2-depleted cells, with minimal effect in BRCA1- or PALB2-proficient cells. RAD52 function was independent of BRCA1 status, as evidenced by the lack of any defect in RAD52 foci formation in BRCA1-depleted cells. Collectively, these findings suggest that RAD52 is an alternative repair pathway of RAD51-mediated HR, and a target for therapy in cells deficient in the BRCA1-PALB2-BRCA2 repair pathway.

  20. Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases.

    PubMed

    Vail, Paris J; Morris, Brian; van Kan, Aric; Burdett, Brianna C; Moyes, Kelsey; Theisen, Aaron; Kerr, Iain D; Wenstrup, Richard J; Eggington, Julie M

    2015-10-01

    Genetic variants of uncertain clinical significance (VUSs) are a common outcome of clinical genetic testing. Locus-specific variant databases (LSDBs) have been established for numerous disease-associated genes as a research tool for the interpretation of genetic sequence variants to facilitate variant interpretation via aggregated data. If LSDBs are to be used for clinical practice, consistent and transparent criteria regarding the deposition and interpretation of variants are vital, as variant classifications are often used to make important and irreversible clinical decisions. In this study, we performed a retrospective analysis of 2017 consecutive BRCA1 and BRCA2 genetic variants identified from 24,650 consecutive patient samples referred to our laboratory to establish an unbiased dataset representative of the types of variants seen in the US patient population, submitted by clinicians and researchers for BRCA1 and BRCA2 testing. We compared the clinical classifications of these variants among five publicly accessible BRCA1 and BRCA2 variant databases: BIC, ClinVar, HGMD (paid version), LOVD, and the UMD databases. Our results show substantial disparity of variant classifications among publicly accessible databases. Furthermore, it appears that discrepant classifications are not the result of a single outlier but widespread disagreement among databases. This study also shows that databases sometimes favor a clinical classification when current best practice guidelines (ACMG/AMP/CAP) would suggest an uncertain classification. Although LSDBs have been well established for research applications, our results suggest several challenges preclude their wider use in clinical practice.

  1. Use of expression data and the CGEMS genome-wide breast cancer association study to identify genes that may modify risk in BRCA1/2 mutation carriers.

    PubMed

    Walker, Logan C; Waddell, Nic; Ten Haaf, Anette; Grimmond, Sean; Spurdle, Amanda B

    2008-11-01

    Germline mutations in BRCA1 or BRCA2 confer an increased lifetime risk of developing breast or ovarian cancer, but variable penetrance suggests that cancer susceptibility is influenced in part by modifier genes. Microarray expression profiling was conducted for 69 irradiated lymphoblastoid cell lines derived from healthy controls, or from cancer-affected women with a strong family history of breast and ovarian cancer carrying pathogenic mutations in BRCA1 or BRCA2, or with no BRCA1/2 mutations (BRCAX). Genes discriminating between BRCA1, BRCA2 or BRCAX and controls were stratified based on irradiation response and/or cell cycle involvement. Gene lists were aligned against genes tagged with single nucleotide polymorphisms (SNPs) determined by the Cancer Genetic Markers of Susceptibility (CGEMS) Breast Cancer Whole Genome Association Scan to be nominally associated with breast cancer risk. Irradiation responsive genes whose expression correlated with BRCA1 and/or BRCA2 mutation status were more likely to be tagged by risk-associated SNPs in the CGEMS dataset (BRCA1, P = 0.0005; BRCA2, P = 0.01). In contrast, irradiation responsive genes correlating with BRCAX status were not enriched in the CGEMS dataset. Classification of expression data by involvement in cell cycle processes did not enrich for genes tagged by risk-associated SNPs, for BRCA1, BRCA2 or BRCAX groups. Using a novel combinatorial approach, we have identified a subset of irradiation responsive genes as high priority candidate BRCA1/2 modifier genes. Similar approaches may be used to identify genes and underlying genetic risk factors that interact with exogenous stimulants to cause or modify any disease, without a priori knowledge of the pathways involved.

  2. BRCA mutations and survival in breast cancer: an updated systematic review and meta-analysis.

    PubMed

    Zhu, Yaning; Wu, Jian; Zhang, Chengwan; Sun, Suan; Zhang, Jian; Liu, Wenjie; Huang, Jian; Zhang, Zhihong

    2016-10-25

    BRCA mutations occur frequently in breast cancer (BC), but their prognostic impact on outcomes of BC has not been determined. We conducted an updated meta-analysis on the association between BRCA mutations and survival in patients with BC. Electronic databases were searched. The primary outcome measure was overall survival (OS), and the secondary outcome measures included breast cancer-specific survival (BCSS) and event-free survival (EFS). Hazard ratios (HR) and 95% confidence interval (CI) were abstracted and pooled with random-effect modeling. Data from 297, 402 patients with BC were pooled from 34 studies. The median prevalence rates of BRCA1 and BRCA2 mutations were 14.5% and 8.3%, respectively. BRCA mutations were associated with worse OS (BRCA1: HR = 1.69, 95% CI, 1.35 to 2.12, p < 0.001; BRCA2: HR = 1.50, 95% CI 1.03 to 2.19, p = 0.034). However, this did not translate into poor BCSS (BRCA1: HR = 1.14, 95% CI, 0.81 to 1.16, p = 0.448; BRCA2: HR = 1.16; 95% CI 0.82 to 1.66, p = 0.401) or EFS (BRCA1: HR = 1.10, 95% CI, 0.86 to 1.41, p = 0.438; BRCA2: HR= 1.09; 95% CI 0.81 to 1.47, p = 0.558). Several studies analyzed BRCA1 and BRCA2 mutations together and found no impact on OS (HR = 1.21; 95% CI, 0.73 to 2.00, p = 0.454) or EFS (HR = 0.94; 95% CI, 0.60 to 1.48, p = 0.787). BRCA1 and BRCA2 mutations were associated with poor OS in patients with BC, but had no significant impact on BCSS or EFS. An improved survival was observed in BC patients who had BRCA1 mutation and treated with endocrinotherapy. The results may have therapeutic and prognostic implications important for BRCA mutation carriers with BC.

  3. Characterization of three alternative transcripts of the BRCA1 gene in patients with breast cancer and a family history of breast and/or ovarian cancer who tested negative for pathogenic mutations.

    PubMed

    Gambino, Gaetana; Tancredi, Mariella; Falaschi, Elisabetta; Aretini, Paolo; Caligo, Maria Adelaide

    2015-04-01

    The study of BRCA1 and BRCA2 genes and their alterations has been essential to the understanding of the development of familial breast and ovarian cancers. Many of the variants identified have an unknown pathogenic significance. These include variants which determine alternative mRNA splicing, identified in the intronic regions and those are capable of destroying the splicing ability. The aim of this study was to detect BRCA1/BRCA2 aberrant transcripts resulting from alternative splicing, in women with a known family history and/or early onset of breast and/or ovarian cancer, tested wild-type for BRCA1 and BRCA2. The identification and characterization of aberrant transcripts through the analysis of mRNA levels in blood lymphocytes may help us to recognize families otherwise misclassified as wild-type BRCA1 and BRCA2. Blood samples were collected from 13 women that had a family history of breast and/or ovarian cancer and tested negative for pathogenic mutations in the BRCA1 and BRCA2 genes. Total RNA was analyzed for the presence of BRCA1 and BRCA2 naturally occurring and pathological transcripts using RT-PCR. In 2 out of the 13 samples, 2 alternative transcripts of the BRCA1 gene were identified. These were probably pathogenic as they lacked exon 17 and exon 15, respectively, giving rise to a truncated protein. In addition to these, we identified the Δ17-19 transcript in 1 patient, which gives rise to a protein with an in-frame deletion of 69 amino acids. In conclusion, this study on alternative transcripts of the BRCA1 and BRCA2 genes revealed the presence of isoforms (prevalence of 15%) in blood samples from women with breast and ovarian cancer that were probably pathogenic, that were not detected by conventional methods of mutation screening based on direct sequencing of all coding regions, intron-exons junctions and MLPA analysis.

  4. Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients

    PubMed Central

    2014-01-01

    Background Germ line mutations in BRCA1 and BRCA2 (BRCA1/2) and other susceptibility genes have been identified as genetic causes of hereditary breast and ovarian cancer (HBOC). To identify the disease-causing mutations in a cohort of 120 Brazilian women fulfilling criteria for HBOC, we carried out a comprehensive screening of BRCA1/2, TP53 R337H, CHEK2 1100delC, followed by an analysis of copy number variations in 14 additional breast cancer susceptibility genes (PTEN, ATM, NBN, RAD50, RAD51, BRIP1, PALB2, MLH1, MSH2, MSH6, TP53, CDKN2A, CDH1 and CTNNB1). Methods Capillary sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for detecting point mutations and copy number variations (CNVs), respectively, for the BRCA1 and BRCA2 genes; capillary sequencing was used for point mutation for both variants TP53 R337H and CHEK2 1100delC, and finally array comparative genomic hybridization (array-CGH) was used for identifying CNVs in the 14 additional genes. Results The positive detection rate in our series was 26%. BRCA1 pathogenic mutations were found in 20 cases, including two cases with CNVs, whereas BRCA2 mutations were found in 7 cases. We also found three patients with the TP53 R337H mutation and one patient with the CHEK2 1100delC mutation. Seven (25%) pathogenic mutations in BRCA1/2 were firstly described, including a splice-site BRCA1 mutation for which pathogenicity was confirmed by the presence of an aberrant transcript showing the loss of the last 62 bp of exon 7. Microdeletions of exon 4 in ATM and exon 2 in PTEN were identified in BRCA2-mutated and BRCA1/2-negative patients, respectively. Conclusions In summary, our results showed a high frequency of BRCA1/2 mutations and a higher prevalence of BRCA1 (64.5%) gene. Moreover, the detection of the TP53 R337H variant in our series and the fact that this variant has a founder effect in our population prompted us to suggest that all female breast cancer patients with clinical criteria

  5. Mutations and polymorphic BRCA variants transmission in breast cancer familial members.

    PubMed

    Pilato, Brunella; Martinucci, Marianna; Danza, Katia; Pinto, Rosamaria; Petriella, Daniela; Lacalamita, Rosanna; Bruno, Michele; Lambo, Rossana; D'Amico, Cosimo; Paradiso, Angelo; Tommasi, Stefania

    2011-02-01

    We previously showed that about 80% of breast cancer patients at high risk to carry mutation in BRCA genes presented at least one polymorphism in these genes which resulted potentially harmful by in silico analysis. In the present paper, the genealogic transmission of those polymorphic coding and noncoding variants of BRCA genes in family's members has been investigated. Thirty families, enrolled within the Genetic Counselling Program of our Institute, with probands and at least one-first degree relative (n = 67 family members) available, have been studied for both BRCA1 and BRCA2 pathological mutation and polymorphic variants' transmission. Ten and 6 probands carried Mendelian transmitted mutations in BRCA1 and BRCA2, respectively. Polymorphic coding and noncoding variants were transmitted in each family's relatives with a frequency ranging from 42 to 100%, with similar rate for each SNP in mutated and nonmutated families with the only exception of BRCA1 K1183R significantly more frequent in mutated families (P = 0.004); conversely, this SNP and BRCA2 N372H, were more frequently present in breast cancer relatives belonging to families in which pathological BRCA mutations were not present. Furthermore, specific haplotypes were transmitted in all relatives as BRCA1 871Leu-1038Gly, present in both BRCA mutated and nonmutated families, while BRCA2 289His-991Asp-IVS14+53 C>T present only in BRCAX families suggesting the harmful role of these SNPs. In conclusion, analysis of SNPs maps and modality of their transmission could identify further susceptibility markers and provide a basis for a better DNA-based cancer classification.

  6. Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles

    PubMed Central

    Gracia-Aznarez, Francisco Javier; Fernandez, Victoria; Pita, Guillermo; Peterlongo, Paolo; Dominguez, Orlando; de la Hoya, Miguel; Duran, Mercedes; Osorio, Ana; Moreno, Leticia; Gonzalez-Neira, Anna; Rosa-Rosa, Juan Manuel; Sinilnikova, Olga; Mazoyer, Sylvie; Hopper, John; Lazaro, Conchi; Southey, Melissa; Odefrey, Fabrice; Manoukian, Siranoush; Catucci, Irene; Caldes, Trinidad; Lynch, Henry T.; Hilbers, Florentine S. M.; van Asperen, Christi J.; Vasen, Hans F. A.; Goldgar, David; Radice, Paolo; Devilee, Peter; Benitez, Javier

    2013-01-01

    The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10) diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC) and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles. PMID:23409019

  7. Skin cancer risk in BRCA1/2 mutation carriers.

    PubMed

    Gumaste, P V; Penn, L A; Cymerman, R M; Kirchhoff, T; Polsky, D; McLellan, B

    2015-06-01

    Women with BRCA1/2 mutations have an elevated risk of breast and ovarian cancer. These patients and their clinicians are often concerned about their risk for other cancers, including skin cancer. Research evaluating the association between BRCA1/2 mutations and skin cancer is limited and has produced inconsistent results. Herein, we review the current literature on the risk of melanoma and nonmelanoma skin cancers in BRCA1/2 mutation carriers. No studies have shown a statistically significant risk of melanoma in BRCA1 families. BRCA2 mutations have been linked to melanoma in large breast and ovarian cancer families, though a statistically significant elevated risk was reported in only one study. Five additional studies have shown some association between BRCA2 mutations and melanoma, while four studies did not find any association. With respect to nonmelanoma skin cancers, studies have produced conflicting results. Given the current state of medical knowledge, there is insufficient evidence to warrant increased skin cancer surveillance of patients with a confirmed BRCA1/2 mutation or a family history of a BRCA1/2 mutation, in the absence of standard risk factors. Nonetheless, suspected BRCA1/2 mutation carriers should be counselled about skin cancer risks and may benefit from yearly full skin examinations.

  8. Asymptomatic gall stones--revisited.

    PubMed

    Supe, Avinash

    2011-01-01

    India has a large burden of individuals harboring asymptomatic gallstones. Based on Markov model decision and cost analysis, selective and concomitant cholecystectomy is recommended for special indications like hemolytic disorders and stones in endemic areas. Expectant management should be adopted in all others. The evolution of laparoscopy should not alter the indications of cholecystectomy. Since more than 90% patients with asymptomatic gallstones remain clinically "silent", routine laparoscopic cholecystectomy is not indicated for the vast majority of subjects with asymptomatic cholelithiasis. Although laparoscopic cholecystectomy has become much safer, there remains associated morbidity and mortality. The risks of the operation outweigh the complications if stones are left in-situ. Patients should be counseled about the natural history and available management options, their advantages and disadvantages, and should be part of the decision making process. Prophylactic routine cholecystectomy for asymptomatic stones is not recommended. However, laparoscopic cholecystectomy should be performed selectively or concomitantly in a specific subgroup of patients.

  9. High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area

    PubMed Central

    Pohlreich, Petr; Zikan, Michal; Stribrna, Jana; Kleibl, Zdenek; Janatova, Marketa; Kotlas, Jaroslav; Zidovska, Jana; Novotny, Jan; Petruzelka, Lubos; Szabo, Csilla; Matous, Bohuslav

    2005-01-01

    Background Germline mutations in the BRCA1 and BRCA2 genes have been shown to account for the majority of hereditary breast and ovarian cancers. The purpose of our study was to estimate the incidence and spectrum of pathogenic mutations in BRCA1/2 genes in high-risk Czech families. Methods A total of 96 Czech families with recurrent breast and/or ovarian cancer and 55 patients considered to be at high-risk but with no reported family history of cancer were screened for mutations in the BRCA1/2 genes. The entire coding sequence of each gene was analyzed using a combination of the protein truncation test and direct DNA sequencing. Results A total of 35 mutations in the BRCA1/2 genes were identified in high-risk families (36.5%). Pathogenic mutations were found in 23.3% of breast cancer families and in 59.4% of families with the occurrence of both breast and ovarian cancer. In addition, four mutations were detected in 31 (12.9%) women with early onset breast cancer. One mutation was detected in seven (14.3%) patients affected with both a primary breast and ovarian cancer and another in three (33.3%) patients with a bilateral breast cancer. A total of 3 mutations in BRCA1 were identified among 14 (21.4%) women with a medullary breast carcinoma. Of 151 analyzed individuals, 35 (23.2%) carried a BRCA1 mutation and 9 (6.0%) a BRCA2 mutation. One novel truncating mutation was found in BRCA1 (c.1747A>T) and two in BRCA2 (c.3939delC and c.5763dupT). The 35 identified BRCA1 mutations comprised 13 different alterations. Three recurrent mutations accounted for 71.4% of unrelated individuals with detected gene alterations. The BRCA1 c.5266dupC (5382insC) was detected in 51.4% of mutation positive women. The mutations c.3700_3704del5 and c.181T>G (300T>G) contributed to 11.4% and 8.6% of pathogenic mutations, respectively. A total of eight different mutations were identified in BRCA2. The novel c.5763dupT mutation, which appeared in two unrelated families, was the only recurrent

  10. Rad18 is required for functional interactions between FANCD2, BRCA2, and Rad51 to repair DNA topoisomerase 1-poisons induced lesions and promote fork recovery

    PubMed Central

    Tripathi, Kaushlendra; Mani, Chinnadurai; Clark, David W; Palle, Komaraiah

    2016-01-01

    Camptothecin (CPT) and its analogues are chemotherapeutic agents that covalently and reversibly link DNA Topoisomerase I to its nicked DNA intermediate eliciting the formation of DNA double strand breaks (DSB) during replication. The repair of these DSB involves multiple DNA damage response and repair proteins. Here we demonstrate that CPT-induced DNA damage promotes functional interactions between BRCA2, FANCD2, Rad18, and Rad51 to repair the replication-associated DSB through homologous recombination (HR). Loss of any of these proteins leads to equal disruption of HR repair, causes chromosomal aberrations and sensitizes cells to CPT. Rad18 appears to function upstream in this repair pathway as its downregulation prevents activation of FANCD2, diminishes BRCA2 and Rad51 protein levels, formation of nuclear foci of all three proteins and recovery of stalled or collapsed replication forks in response to CPT. Taken together this work further elucidates the complex interplay of DNA repair proteins in the repair of replication-associated DSB. PMID:26871286

  11. Small-molecule inhibitors identify the RAD52-ssDNA interaction as critical for recovery from replication stress and for survival of BRCA2 deficient cells

    PubMed Central

    Hengel, Sarah R; Malacaria, Eva; Folly da Silva Constantino, Laura; Bain, Fletcher E; Diaz, Andrea; Koch, Brandon G; Yu, Liping; Wu, Meng; Pichierri, Pietro; Spies, M Ashley; Spies, Maria

    2016-01-01

    The DNA repair protein RAD52 is an emerging therapeutic target of high importance for BRCA-deficient tumors. Depletion of RAD52 is synthetically lethal with defects in tumor suppressors BRCA1, BRCA2 and PALB2. RAD52 also participates in the recovery of the stalled replication forks. Anticipating that ssDNA binding activity underlies the RAD52 cellular functions, we carried out a high throughput screening campaign to identify compounds that disrupt the RAD52-ssDNA interaction. Lead compounds were confirmed as RAD52 inhibitors in biochemical assays. Computational analysis predicted that these inhibitors bind within the ssDNA-binding groove of the RAD52 oligomeric ring. The nature of the inhibitor-RAD52 complex was validated through an in silico screening campaign, culminating in the discovery of an additional RAD52 inhibitor. Cellular studies with our inhibitors showed that the RAD52-ssDNA interaction enables its function at stalled replication forks, and that the inhibition of RAD52-ssDNA binding acts additively with BRCA2 or MUS81 depletion in cell killing. DOI: http://dx.doi.org/10.7554/eLife.14740.001 PMID:27434671

  12. Individual and Combined Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predict Shorter Survival of Soft Tissue Sarcoma Patients

    PubMed Central

    Park, See-Hyoung; Park, Hye Jeong; Wang, Sung Il; Park, Ho Sung; Lee, Ho; Kwon, Keun Sang; Moon, Woo Sung; Lee, Dong Geun; Kim, Jung Ryul; Jang, Kyu Yun

    2016-01-01

    DNA damage response (DDR) molecules are protective against genotoxic stresses. DDR molecules are also involved in the survival of cancer cells in patients undergoing anti-cancer therapies. Therefore, DDR molecules are potential markers of cancer progression in addition to being potential therapeutic targets. In this study, we evaluated the immunohistochemical expression of PARP1, γH2AX, BRCA1, and BRCA2 and their prognostic significance in 112 cases of soft tissue sarcoma (STS). The expression of PARP1, γH2AX, BRCA1, and BRCA2 were significantly associated with each other and were associated with higher tumor stage and presence of distant metastasis. The expression of PARP1, γH2AX, and BRCA2 were significantly associated with shorter disease-specific survival (DSS) and event-free survival (EFS) by univariate analysis. BRCA1 expression was associated with shorter DSS. Multivariate analysis revealed the expression of PARP1 and γH2AX to be independent indicators of poor prognosis of DSS and EFS. BRCA2 expression was an independent indicator of poor prognosis of DSS. In addition, the combined expressional patterns of PARP1, γH2AX, BRCA1, and BRCA2 (CSddrm) were independent prognostic predictors of DSS (P < 0.001) and EFS (P = 0.016). The ten-year DSS rate of the CSddrm-low, CSddrm-intermediate, and CSddrm-high subgroups were 81%, 26%, and 0%, respectively. In conclusion, this study demonstrates that the individual and combined expression patterns of the DDR molecules PARP1, γH2AX, BRCA1, and BRCA2 could be predictive of the prognosis of STS patients and suggests that controlling the activity of these DDR molecules could be employed in new therapeutic stratagems for the treatment of STS. PMID:27643881

  13. BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging.

    PubMed

    Oktay, Kutluk; Turan, Volkan; Titus, Shiny; Stobezki, Robert; Liu, Lin

    2015-09-01

    Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related decline in reproductive success have not been fully addressed. BRCA is known to be involved in homologous DNA recombination and plays an essential role in double-strand DNA break repair. Given the growing body of laboratory and clinical evidence, we performed a systematic review on the current understanding of the role of DNA repair in human reproduction. We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo results and prospective studies. Because decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging, unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and because of the masking of most severe cases by prophylactic oophorectomy or cancer, it is less likely one would see an effect of BRCA mutations on fertility until later in reproductive age. The impact of BRCA2 mutations on reproductive function may be less visible because of the delayed decline in the function of normal BRCA2 allele. BRCA1 function and ataxia-telangiectasia-mutated (ATM)-mediated DNA repair may also be important in the pathogenesis of age-induced increase in aneuploidy. BRCA1 is required for meiotic spindle assembly, and cohesion function between sister chromatids is also regulated by ATM family member proteins. Taken together, these findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian aging.

  14. Treatment of asymptomatic catecholaminergic polymorphic ventricular tachycardia.

    PubMed

    Obeyesekere, Manoj N; Sy, Raymond W; Leong-Sit, Peter; Gula, Lorne J; Yee, Raymond; Skanes, Allan C; Klein, George J; Krahn, Andrew D

    2012-05-01

    Catecholaminergic polymorphic ventricular tachycardia is a rare genetic disorder caused by mutations in genes involved in the intracellular calcium homeostasis of cardiac cells. Affected patients typically present with life-threatening ventricular arrhythmias precipitated by emotional/physical stress. The diagnosis is based on the demonstration of polymorphic or bidirectional ventricular tachycardia associated with adrenergic stress. Genetic testing can be confirmatory in some patients. Treatment for catecholaminergic polymorphic ventricular tachycardia includes medical and surgical efforts to suppress the effects of epinephrine at the myocardial level and/or modulation of calcium homeostasis. Mortality is high when untreated and sudden cardiac death may be the first manifestation of the disease. First-degree relatives of a proband should be offered genetic testing if the causal mutation is known. If the family mutation is not known, relatives should be clinically evaluated with provocative testing. In the absence of rigorous trials, prophylactic treatment of the asymptomatic catecholaminergic polymorphic ventricular tachycardia patient appears to reduce morbidity and mortality.

  15. Prostate cancer screening characteristics in men with BRCA1/2 mutations attending a high-risk prevention clinic

    PubMed Central

    Walker, Richard; Louis, Alyssa; Berlin, Alejandro; Horsburgh, Sheri; Bristow, Robert G.; Trachtenberg, John

    2014-01-01

    Introduction: The prostate-specific antigen (PSA) era and resultant early detection of prostate cancer has presented clinicians with the challenge of distinguishing indolent from aggressive tumours. Mutations in the BRCA1/2 genes have been associated with prostate cancer risk and prognosis. We describe the prostate cancer screening characteristics of BRCA1/2 mutation carriers, who may be classified as genetically-defined high risk, as compared to another high-risk cohort of men with a family history of prostate cancer to evaluate the utility of a targeted screening approach for these men. Methods: We reviewed patient demographics, clinical screening characteristics, pathological features, and treatment outcomes between a group of BRCA1 or BRCA2 mutation carriers and age-matched men with a family history of prostate cancer followed at our institutional Prostate Cancer Prevention Clinic from 1995 to 2012. Results: Screening characteristics were similar between the mutation carriers (n = 53) and the family history group (n = 53). Some cancers would be missed in both groups by using a PSA cut-off of >4 ug/L. While cancer detection was higher in the family history group (21% vs. 15%), the mutation carrier group was more likely to have intermediate- or high-risk disease (88% vs. 36%). BRCA2 mutation carriers were more likely to have aggressive disease, biological recurrence, and distant metastasis. Conclusions: In our cohort, regular screening appears justified for detecting prostate cancer in BRCA1 and BRCA2 carriers and other high-risk populations. Lowering PSA cut-offs and defining monitoring of PSA velocity as part of the screening protocol may be useful. BRCA2 is associated with more aggressive disease, while the outcome for BRCA1 mutation carriers requires further study. Large multinational studies will be important to define screening techniques for this unique high-risk population. PMID:25485004

  16. Efficiency of BRCAPRO and Myriad II mutation probability thresholds versus cancer history criteria alone for BRCA1/2 mutation detection.

    PubMed

    van Harssel, J J T; van Roozendaal, C E P; Detisch, Y; Brandão, R D; Paulussen, A D C; Zeegers, M; Blok, M J; Gómez García, E B

    2010-06-01

    Considerable differences exist amongst countries in the mutation probability methods and thresholds used to select patients for BRCA1/2 genetic screening. In order to assess the added value of mutation probability methods, we have retrospectively calculated the BRCAPRO and Myriad II probabilities in 306 probands who had previously been selected for DNA-analysis according to criteria based on familial history of cancer. DNA-analysis identified 52 mutations (16.9%) and 11 unclassified variants (UVs, 3.6%). Compared to cancer history, a threshold > or = 10% with BRCAPRO or with Myriad II excluded about 40% of the patients from analysis, including four with a mutation and probabilities <10% with both programs. All four probands had a BRCA2 mutation. BRCAPRO and Myriad II showed similar specificity at 10% threshold, overall BRCAPRO was more sensitive than Myriad II for the detection of mutations. Only two of the probands with an UV had probabilities >20% with BRCAPRO and Myriad II. In summary, BRCAPRO and Myriad II are more efficient than cancer history alone to exclude patients without a mutation. BRCAPRO performs better for the detection of BRCA1 mutations than of BRCA2 mutations. The Myriad II scores provided no additional information than the BRCAPRO scores alone for the detection of patients with a mutation. The use of thresholds excluded from analysis the majority of patients carrying an UV.

  17. Asymptomatic Young Man with Danon Disease

    PubMed Central

    Parikh, Parag; Mahboob, Mohammad; Arrighi, James A.; Atalay, Michael K.; Rowin, Ethan J.; Maron, Martin S.

    2014-01-01

    Danon disease is a rare, codominant X-linked genetic disorder characterized by the triad of left ventricular hypertrophy, mental retardation, and peripheral myopathy. This disease is caused by mutations in the gene that encodes lysosomal associated membrane protein 2 (LAMP2), a deficiency of which results in the accumulation of autophagic granular débris within the vacuoles of muscle cells. This is a report of an asymptomatic 19-year-old man with Danon disease in the absence of mental retardation or clinically significant skeletal myopathy. This case underscores the importance of accurate diagnosis of unexplained left ventricular hypertrophy, in order to establish an appropriate treatment plan and to advise genetic counseling. PMID:24955057

  18. Asymptomatic young man with Danon disease.

    PubMed

    Kim, Jiwon; Parikh, Parag; Mahboob, Mohammad; Arrighi, James A; Atalay, Michael K; Rowin, Ethan J; Maron, Martin S

    2014-06-01

    Danon disease is a rare, codominant X-linked genetic disorder characterized by the triad of left ventricular hypertrophy, mental retardation, and peripheral myopathy. This disease is caused by mutations in the gene that encodes lysosomal associated membrane protein 2 (LAMP2), a deficiency of which results in the accumulation of autophagic granular débris within the vacuoles of muscle cells. This is a report of an asymptomatic 19-year-old man with Danon disease in the absence of mental retardation or clinically significant skeletal myopathy. This case underscores the importance of accurate diagnosis of unexplained left ventricular hypertrophy, in order to establish an appropriate treatment plan and to advise genetic counseling.

  19. Genotype-Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers.

    PubMed

    Bayraktar, Soley; Jackson, Michelle; Gutierrez-Barrera, Angelica M; Liu, Diane; Meric-Bernstam, Funda; Brandt, Amanda; Woodson, Ashley; Litton, Jennifer; Lu, Karen H; Valero, Vicente; Arun, Banu K

    2015-01-01

    The genotype-phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi-ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi-Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0-12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation-specific counseling and be more aggressively managed for risk reduction.

  20. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

    SciTech Connect

    Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; Ramakrishna, Manasa; Glodzik, Dominik; Zou, Xueqing; Martincorena, Inigo; Alexandrov, Ludmil B.; Martin, Sancha; Wedge, David C.; Van Loo, Peter; Ju, Young Seok; Smid, Marcel; Brinkman, Arie B.; Morganella, Sandro; Aure, Miriam R.; Lingjærde, Ole Christian; Langerod, Anita; Ringner, Markus; Ahn, Sung -Min; Boyault, Sandrine; Brock, Jane E.; Broeks, Annegien; Butler, Adam; Desmedt, Christine; Dirix, Luc; Dronov, Serge; Fatima, Aquila; Foekens, John A.; Gerstung, Moritz; Hooijer, Gerrit K. J.; Jang, Se Jin; Jones, David R.; Kim, Hyung -Yong; King, Tari A.; Krishnamurthy, Savitri; Lee, Hee Jin; Lee, Jeong -Yeon; Li, Yilong; McLaren, Stuart; Menzies, Andrew; Mustonen, Ville; O’Meara, Sarah; Pauporte, Iris; Pivot, Xavier; Purdie, Colin A.; Raine, Keiran; Ramakrishnan, Kamna; Rodríguez-Gonzalez, F. German; Romieu, Gilles; Sieuwerts, Anieta M.; Simpson, Peter T.; Shepherd, Rebecca; Stebbings, Lucy; Stefansson, Olafur A.; Teague, Jon; Tommasi, Stefania; Treilleux, Isabelle; Van den Eynden, Gert G.; Vermeulen, Peter; Vincent-Salomon, Anne; Yates, Lucy; Caldas, Carlos; Veer, Laura van’t; Tutt, Andrew; Knappskog, Stian; Tan, Benita Kiat Tee; Jonkers, Jos; Borg, Ake; Ueno, Naoto T.; Sotiriou, Christos; Viari, Alain; Futreal, P. Andrew; Campbell, Peter J.; Span, Paul N.; Van Laere, Steven; Lakhani, Sunil R.; Eyfjord, Jorunn E.; Thompson, Alastair M.; Birney, Ewan; Stunnenberg, Hendrik G.; van de Vijver, Marc J.; Martens, John W. M.; Borresen-Dale, Anne -Lise; Richardson, Andrea L.; Kong, Gu; Thomas, Gilles; Stratton, Michael R.

    2016-05-02

    Here, we analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

  1. Landscape of somatic mutations in 560 breast cancer whole genome sequences

    PubMed Central

    Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; Ramakrishna, Manasa; Glodzik, Dominik; Zou, Xueqing; Martincorena, Inigo; Alexandrov, Ludmil B.; Martin, Sancha; Wedge, David C.; Van Loo, Peter; Ju, Young Seok; Smid, Marcel; Brinkman, Arie B; Morganella, Sandro; Aure, Miriam R.; Lingjærde, Ole Christian; Langerød, Anita; Ringnér, Markus; Ahn, Sung-Min; Boyault, Sandrine; Brock, Jane E.; Broeks, Annegien; Butler, Adam; Desmedt, Christine; Dirix, Luc; Dronov, Serge; Fatima, Aquila; Foekens, John A.; Gerstung, Moritz; Hooijer, Gerrit KJ; Jang, Se Jin; Jones, David R.; Kim, Hyung-Yong; King, Tari A.; Krishnamurthy, Savitri; Lee, Hee Jin; Lee, Jeong-Yeon; Li, Yilong; McLaren, Stuart; Menzies, Andrew; Mustonen, Ville; O’Meara, Sarah; Pauporté, Iris; Pivot, Xavier; Purdie, Colin A.; Raine, Keiran; Ramakrishnan, Kamna; Rodríguez-González, F. Germán; Romieu, Gilles; Sieuwerts, Anieta M.; Simpson, Peter T; Shepherd, Rebecca; Stebbings, Lucy; Stefansson, Olafur A; Teague, Jon; Tommasi, Stefania; Treilleux, Isabelle; Van den Eynden, Gert G.; Vermeulen, Peter; Vincent-Salomon, Anne; Yates, Lucy; Caldas, Carlos; van’t Veer, Laura; Tutt, Andrew; Knappskog, Stian; Tan, Benita Kiat Tee; Jonkers, Jos; Borg, Åke; Ueno, Naoto T; Sotiriou, Christos; Viari, Alain; Futreal, P. Andrew; Campbell, Peter J; Span, Paul N.; Van Laere, Steven; Lakhani, Sunil R; Eyfjord, Jorunn E.; Thompson, Alastair M.; Birney, Ewan; Stunnenberg, Hendrik G; van de Vijver, Marc J; Martens, John W.M.; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Kong, Gu; Thomas, Gilles; Stratton, Michael R.

    2016-01-01

    We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer. PMID:27135926

  2. TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.

    PubMed

    Chien, Jeremy; Sicotte, Hugues; Fan, Jian-Bing; Humphray, Sean; Cunningham, Julie M; Kalli, Kimberly R; Oberg, Ann L; Hart, Steven N; Li, Ying; Davila, Jaime I; Baheti, Saurabh; Wang, Chen; Dietmann, Sabine; Atkinson, Elizabeth J; Asmann, Yan W; Bell, Debra A; Ota, Takayo; Tarabishy, Yaman; Kuang, Rui; Bibikova, Marina; Cheetham, R Keira; Grocock, Russell J; Swisher, Elizabeth M; Peden, John; Bentley, David; Kocher, Jean-Pierre A; Kaufmann, Scott H; Hartmann, Lynn C; Shridhar, Viji; Goode, Ellen L

    2015-08-18

    To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC.

  3. Prevalence of BRCA1 Mutations in Familial and Sporadic Greek Ovarian Cancer Cases

    PubMed Central

    Stavropoulou, Alexandra V.; Fostira, Florentia; Pertesi, Maroulio; Tsitlaidou, Marianthi; Voutsinas, Gerassimos E.; Triantafyllidou, Olga; Bamias, Aristotelis; Dimopoulos, Meletios A.; Timotheadou, Eleni; Pectasides, Dimitrios; Christodoulou, Christos; Klouvas, George; Papadimitriou, Christos; Makatsoris, Thomas; Pentheroudakis, George; Aravantinos, Gerasimos; Karydakis, Vassilis; Yannoukakos, Drakoulis; Fountzilas, George; Konstantopoulou, Irene

    2013-01-01

    Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23–24 and exon 24). In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6%) of familial cancer cases and in 27/592 (4.6%) of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%). The majority of BRCA1 carriers (71.2%) presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer. PMID:23536787

  4. Two PALB2 germline mutations found in both BRCA1+ and BRCAx familial breast cancer.

    PubMed

    Downs, Bradley; Kim, Yeong C; Xiao, Fengxia; Snyder, Carrie; Chen, Peixian; Fleissner, Elizabeth A; Becirovic, Dina; Wen, Hongxiu; Sherman, Simon; Cowan, Kenneth H; Lynch, Henry T; Wang, San Ming

    2015-05-01

    Partner and localizer of BRCA2 (PALB2), plays an important functional role in DNA damage repair. Recent studies indicate that germline mutations in PALB2 predispose individuals to a high risk of developing familial breast cancer. Therefore, comprehensive identification of PALB2 germline mutations is potentially important for understanding their roles in tumorigenesis and for testing their potential utility as clinical targets. Most of the previous studies of PALB2 have focused on familial breast cancer cases with normal/wild-type BRCA1 and BRCA2 (BRCAx). We hypothesize that PALB2 genetic mutations also exist in individuals with BRCA mutations (BRCA+). To test this hypothesis, PALB2 germline mutations were screened in 107 exome data sets collected from familial breast cancer families who were either BRCA1+ or BRCAx. Two novel heterozygous mutations predicted to alter the function of PALB2 were identified (c.2014G>C, p.E672Q and c.2993G>A, p.G998E). Notably, both of these mutations co-existed in BRCA1+ and BRCA1x families. These studies show that mutations in PALB2 can occur independent of the status of BRCA1 mutations, and they highlight the importance to include BRCA1+ families in PALB2 mutation screens.

  5. Human INO80/YY1 chromatin remodeling complex transcriptionally regulates the BRCA2- and CDKN1A-interacting protein (BCCIP) in cells.

    PubMed

    Su, Jiaming; Sui, Yi; Ding, Jian; Li, Fuqiang; Shen, Shuang; Yang, Yang; Lu, Zeming; Wang, Fei; Cao, Lingling; Liu, Xiaoxia; Jin, Jingji; Cai, Yong

    2016-10-01

    The BCCIP (BRCA2- and CDKN1A-interacting protein) is an important cofactor for BRCA2 in tumor suppression. Although the low expression of BCCIP is observed in multiple clinically diagnosed primary tumor tissues such as ovarian cancer, renal cell carcinoma and colorectal carcinoma, the mechanism of how BCCIP is regulated in cells is still unclear. The human INO80/YY1 chromatin remodeling complex composed of 15 subunits catalyzes ATP-dependent sliding of nucleosomes along DNA. Here, we first report that BCCIP is a novel target gene of the INO80/YY1 complex by presenting a series of experimental evidence. Gene expression studies combined with siRNA knockdown data locked candidate genes including BCCIP of the INO80/YY1 complex. Silencing or over-expressing the subunits of the INO80/YY1 complex regulates the expression level of BCCIP both in mRNA and proteins in cells. Also, the functions of INO80/YY1 complex in regulating the transactivation of BCCIP were confirmed by luciferase reporter assays. Chromatin immunoprecipitation (ChIP) experiments clarify the enrichment of INO80 and YY1 at +0.17 kb downstream of the BCCIP transcriptional start site. However, this enrichment is significantly inhibited by either knocking down INO80 or YY1, suggesting the existence of both INO80 and YY1 is required for recruiting the INO80/YY1 complex to BCCIP promoter region. Our findings strongly indicate that BCCIP is a potential target gene of the INO80/YY1 complex.

  6. Mutational analysis of BRCA1/2 gene and pathologic characteristics from Kazakh population with sporadic breast cancer in northwestern China.

    PubMed

    Yang, S Y; Aisimutula, D; Li, H F; Hu, Y; Du, X; Li, J; Luan, M X

    2015-10-27

    Mutations in the BRCA1/2 genes are associated with an increased risk of breast cancer, but no large-scale research have examined the BRCA1/2 mutations in Chinese Kazakh women. We evaluated the frequency and distributions of BRCA1 and BRCA2 gene mutations in Kazakh sporadic breast cancer patients and healthy women in China. The association between the clinical-pathologic features of Kazakh breast cancer patients and BRCA1/2 mutations were also investigated. Two unclassified variants (T539M and T1915M) and 16 polymorphisms were detected in this study, 4 of which (G356A, His743, Asn991Asp, Val1269) were detected more frequently in breast cancer patients than in healthy controls. We observed a higher prevalence of BRCA1/2 common sequence alterations and a large number of Kazakh women carrying multiple co-existing BRCA1/2 mutations. The prevalence of BRCA1 mutations was similar to that of BRCA2 mutations. Although no significant differences were observed, BRCA1/2 carriers were generally younger at diagnosis of wild-type breast cancer patients. BRCA1-associated Kazakh sporadic breast cancers present with high tumor grade, early stage, negative lymph node status, absence of estrogen receptor expression and progesterone-positive status. Estrogen receptor expression was the only predominant histological type in BRCA2 carriers. In this study, we determined the BRCA1 and BRCA2 gene mutation status and determined the association with clinical-pathologic characteristics in a Chinese Kazakh population. Larger population-based screening studies screening the entire coding region of BRCA1/2 are required to evaluate the breast cancer risk induced by the sequence alterations detected in this study.

  7. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis

    PubMed Central

    Bu, Rong; Siraj, Abdul K.; Al‐Obaisi, Khadija A.S.; Beg, Shaham; Al Hazmi, Mohsen; Ajarim, Dahish; Tulbah, Asma; Al‐Dayel, Fouad

    2016-01-01

    Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost‐effective screening strategy. PMID:27082205

  8. Invasion Patterns of Metastatic Extrauterine High-grade Serous Carcinoma With BRCA Germline Mutation and Correlation With Clinical Outcomes.

    PubMed

    Hussein, Yaser R; Ducie, Jennifer A; Arnold, Angela G; Kauff, Noah D; Vargas-Alvarez, Hebert A; Sala, Evis; Levine, Douglas A; Soslow, Robert A

    2016-03-01

    Characteristic histopathologic features have been described in high-grade serous carcinoma associated with BRCA abnormalities (HGSC-BRCA), which are known to have relatively favorable clinical outcomes. The aim of this study was to evaluate the clinical significance of invasion patterns in metastatic HGSC-BRCA cases. Of the 37 cases of advanced-stage HGSC with known BRCA1 or BRCA2 germline mutation retrieved from our institutional files, 23 patients had a germline mutation of BRCA1 and 14 had a BRCA2 mutation. The pattern of invasion at metastatic sites was recorded and classified as a pushing pattern (either predominantly or exclusively), an exclusively micropapillary infiltrative pattern, or an infiltrative pattern composed of papillae, micropapillae, glands, and nests (mixed infiltrative pattern). Histologic evaluation of metastases was performed without knowledge of genotype or clinical outcome. Clinical data were abstracted from medical records. Median age was 56 years (range, 31 to 73 y). All patients presented at stage IIIC or IV and underwent complete surgical staging followed by chemotherapy. All 37 HGSC-BRCA cases showed either pushing pattern metastases (30; 81%) or infiltrative micropapillary metastases (7; 19%). No HGSC-BRCA case exhibited metastases composed solely of mixed infiltrative patterns. Among the 7 infiltrative micropapillary cases, 6 had a BRCA1 germline mutation versus 1 with a BRCA2 mutation. The median time of follow-up was 26 months (range, 13 to 49 mo). All 7 patients with infiltrative micropapillary metastases either experienced recurrence or died of disease (5 recurrences and 2 deaths), which was significantly worse than what was seen in patients with predominantly pushing pattern metastases, of whom 16 of 30 (53%) experienced recurrence (n=14) or died of disease (n=2) (P=0.03). In conclusion, the recognition of different invasion patterns of metastatic extrauterine HGSC-BRCA has prognostic implications. The infiltrative

  9. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

    PubMed

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; de Garibay, Gorka Ruiz; Librado, Pablo; Sánchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Núria; McGuffog, Lesley; Pankratz, Vernon S; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Català, Isabel; Brunet, Joan; Feliubadaló, Lidia; Tornero, Eva; Benítez, Javier; Osorio, Ana; Ramón y Cajal, Teresa; Nevanlinna, Heli; Aittomäki, Kristiina; Arun, Banu K; Toland, Amanda E; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Greene, Mark H; Mai, Phuong L; Nussbaum, Robert L; Andrulis, Irene L; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Barkardottir, Rosa B; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; Van Maerken, Tom; Díez, Orland; Hansen, Thomas V; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldés, Trinidad; Dunning, Alison M; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R; Hogervorst, Frans B L; van der Hout, Annemarie H; Seynaeve, Caroline; van der Luijt, Rob B; Ligtenberg, Marjolijn J L; Devilee, Peter; Wijnen, Juul T; Rookus, Matti A; Meijers-Heijboer, Hanne E J; Blok, Marinus J; van den Ouweland, Ans M W; Aalfs, Cora M; Rodriguez, Gustavo C; Phillips, Kelly-Anne A; Piedmonte, Marion; Nerenstone, Stacy R; Bae-Jump, Victoria L; O'Malley, David M; Ratner, Elena S; Schmutzler, Rita K; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Geschwantler-Kaulich, Daphne; Tea, Muy-Kheng; Pfeiler, Georg; John, Esther M; Miron, Alex; Neuhausen, Susan L; Terry, Mary Beth; Chung, Wendy K; Daly, Mary B; Goldgar, David E; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elisabeth J; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K; Olah, Edith; Narod, Steven A; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N; Hamann, Ute; Spurdle, Amanda B; Healey, Sue; Weitzel, Jeffrey N; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gómez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Léoné, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, François; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M; Maxwell, Christopher A; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lázaro, Conxi; Easton, Douglas F; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J; Antoniou, Antonis C; Pujana, Miguel Angel

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

  10. Modifiers of the Efficacy of Risk-Reducing Salpingo-Oophorectomy for the Prevention of Breast and Ovarian Cancer in Carriers of BRCA1 and BRCA2 Mutations

    DTIC Science & Technology

    2008-05-01

    4 Body : Progress on Research Project Component of Award………………………. 4 Progress on Didactic Training Component of Award………...……………. 5...Goldfrank D, Chuai S, Bernstein JL, Ramon y Cajal T, Lee JB, Alonso MC, Diez O, Baiget M, Kauff ND, Offit K, Robson M. Impact of Mammography on Breast

  11. Law-medicine interfacing: patenting of human genes and mutations.

    PubMed

    Fialho, Arsenio M; Chakrabarty, Ananda M

    2011-08-01

    Mutations, Single Nucleotide Polymorphisms (SNPs), deletions and genetic rearrangements in specific genes in the human genome account for not only our physical characteristics and behavior, but can lead to many in-born and acquired diseases. Such changes in the genome can also predispose people to cancers, as well as significantly affect the metabolism and efficacy of many drugs, resulting in some cases in acute toxicity to the drug. The testing of the presence of such genetic mutations and rearrangements is of great practical and commercial value, leading many of these genes and their mutations/deletions and genetic rearrangements to be patented. A recent decision by a judge in the Federal District Court in the Southern District of New York, has created major uncertainties, based on the revocation of BRCA1 and BRCA2 gene patents, in the eligibility of all human and presumably other gene patents. This article argues that while patents on BRCA1 and BRCA2 genes could be challenged based on a lack of utility, the patenting of the mutations and genetic rearrangements is of great importance to further development and commercialization of genetic tests that can save human lives and prevent suffering, and should be allowed.

  12. Estimate of the penetrance of BRCA mutation and the COS software for the assessment of BRCA mutation probability.

    PubMed

    Berrino, Jacopo; Berrino, Franco; Francisci, Silvia; Peissel, Bernard; Azzollini, Jacopo; Pensotti, Valeria; Radice, Paolo; Pasanisi, Patrizia; Manoukian, Siranoush

    2015-03-01

    We have designed the user-friendly COS software with the intent to improve estimation of the probability of a family carrying a deleterious BRCA gene mutation. The COS software is similar to the widely-used Bayesian-based BRCAPRO software, but it incorporates improved assumptions on cancer incidence in women with and without a deleterious mutation, takes into account relatives up to the fourth degree and allows researchers to consider an hypothetical third gene or a polygenic model of inheritance. Since breast cancer incidence and penetrance increase over generations, we estimated birth-cohort-specific incidence and penetrance curves. We estimated breast and ovarian cancer penetrance in 384 BRCA1 and 229 BRCA2 mutated families. We tested the COS performance in 436 Italian breast/ovarian cancer families including 79 with BRCA1 and 27 with BRCA2 mutations. The area under receiver operator curve (AUROC) was 84.4 %. The best probability threshold for offering the test was 22.9 %, with sensitivity 80.2 % and specificity 80.3 %. Notwithstanding very different assumptions, COS results were similar to BRCAPRO v6.0.

  13. Mutation analysis of PALB2 gene in French breast cancer families.

    PubMed

    Damiola, Francesca; Schultz, Inès; Barjhoux, Laure; Sornin, Valérie; Dondon, Marie-Gabrielle; Eon-Marchais, Séverine; Marcou, Morgane; Caron, Olivier; Gauthier-Villars, Marion; de Pauw, Antoine; Luporsi, Elisabeth; Berthet, Pascaline; Delnatte, Capucine; Bonadona, Valérie; Maugard, Christine; Pujol, Pascal; Lasset, Christine; Longy, Michel; Bignon, Yves-Jean; Fricker, Jean-Pierre; Andrieu, Nadine; Sinilnikova, Olga M; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Muller, Danièle

    2015-12-01

    Several population-based and family-based studies have demonstrated that germline mutations of the PALB2 gene (Partner and Localizer of BRCA2) are associated with an increased risk of breast cancer. Distinct mutation frequencies and spectrums have been described depending on the population studied. Here we describe the first complete PALB2 coding sequence screening in the French population. We screened the complete coding sequence and intron-exon boundaries of PALB2, using the EMMA technique, to assess the contribution of pathogenic mutations in a set of 835 familial breast cancer cases and 662 unrelated controls from the French national study GENESIS and the Paul Strauss Cancer Centre, all previously tested negative for BRCA1 and BRCA2 pathogenic mutations. Our analysis revealed the presence of four novel deleterious mutations: c.1186insT, c.1857delT and c.2850delC in three cases, c.3418dupT in one control. In addition, we identified two in-frame insertion/deletion, 19 missense substitutions (two of them predicted as pathogenic), 9 synonymous variants, 28 variants located in introns and 2 in UTRs, as well as frequent variants. Truncating PALB2 mutations were found in 0.36% of familial breast cancer cases, a frequency lower than the one detected in comparable studies in other populations (0.73-3.40%). This suggests a small but significant contribution of PALB2 mutations to the breast cancer susceptibility in the French population.

  14. Reevaluation of the BRCA2 truncating allele c.9976A > T (p.Lys3326Ter) in a familial breast cancer context.

    PubMed

    Thompson, Ella R; Gorringe, Kylie L; Rowley, Simone M; Li, Na; McInerny, Simone; Wong-Brown, Michelle W; Devereux, Lisa; Li, Jason; Trainer, Alison H; Mitchell, Gillian; Scott, Rodney J; James, Paul A; Campbell, Ian G

    2015-10-12

    The breast cancer predisposition gene, BRCA2, has a large number of genetic variants of unknown effect. The variant rs11571833, an A > T transversion in the final exon of the gene that leads to the creation of a stop codon 93 amino acids early (K3326*), is reported as a neutral polymorphism but there is some evidence to suggest an association with an increased risk of breast cancer. We assessed whether this variant was enriched in a cohort of breast cancer cases ascertained through familial cancer clinics compared to population-based non-cancer controls using a targeted sequencing approach. We identified the variant in 66/2634 (2.5%) cases and 33/1996 (1.65%) controls, indicating an enrichment in the breast cancer cases (p = 0.047, OR 1.53, 95% CI 1.00-2.34). This data is consistent with recent iCOGs data suggesting that this variant is not neutral with respect to breast cancer risk. rs11571833 may need to be included in SNP panels for evaluating breast cancer risk.

  15. Nedd8-activating enzyme inhibitor MLN4924 provides synergy with mitomycin C through interactions with ATR, BRCA1/BRCA2, and chromatin dynamics pathways.

    PubMed

    Garcia, Khristofer; Blank, Jonathan L; Bouck, David C; Liu, Xiaozhen J; Sappal, Darshan S; Hather, Greg; Cosmopoulos, Katherine; Thomas, Michael P; Kuranda, Mike; Pickard, Michael D; Liu, Ray; Bandi, Syamala; Smith, Peter G; Lightcap, Eric S

    2014-06-01

    MLN4924 is an investigational small-molecule inhibitor of the Nedd8-activating enzyme currently in phase I clinical trials. MLN4924 induces DNA damage via rereplication in most cell lines. This distinct mechanism of DNA damage may affect its ability to combine with standard-of-care agents and may affect the clinical development of MLN4924. As such, we studied its interaction with other DNA-damaging agents. Mitomycin C, cisplatin, cytarabine, UV radiation, SN-38, and gemcitabine demonstrated synergy in combination with MLN4924 in vitro. The combination of mitomycin C and MLN4924 was shown to be synergistic in a mouse xenograft model. Importantly, depletion of genes within the ataxia telangiectasia and Rad3 related (ATR) and BRCA1/BRCA2 pathways, chromatin modification, and transcription-coupled repair reduced the synergy between mitomycin C and MLN4924. In addition, comet assay demonstrated increased DNA strand breaks with the combination of MLN4924 and mitomycin C. Our data suggest that mitomycin C causes stalled replication forks, which when combined with rereplication induced by MLN4924 results in frequent replication fork collisions, leading to cell death. This study provides a straightforward approach to understand the mechanism of synergy, which may provide useful information for the clinical development of these combinations.

  16. Reevaluation of the BRCA2 truncating allele c.9976A > T (p.Lys3326Ter) in a familial breast cancer context

    PubMed Central

    Thompson, Ella R.; Gorringe, Kylie L.; Rowley, Simone M.; Li, Na; McInerny, Simone; Wong-Brown, Michelle W.; Devereux, Lisa; Li, Jason; Campbell, Ian G.; Devereux, Lisa; Hopper, John; Pridmore, Vicki; Kavanagh, Anne; Mitchell, Gillian; Mann, Bruce; Fox, Stephen; Trainer, Alison H.; Mitchell, Gillian; Scott, Rodney J.; James, Paul A.; Campbell, Ian G.

    2015-01-01

    The breast cancer predisposition gene, BRCA2, has a large number of genetic variants of unknown effect. The variant rs11571833, an A > T transversion in the final exon of the gene that leads to the creation of a stop codon 93 amino acids early (K3326*), is reported as a neutral polymorphism but there is some evidence to suggest an association with an increased risk of breast cancer. We assessed whether this variant was enriched in a cohort of breast cancer cases ascertained through familial cancer clinics compared to population-based non-cancer controls using a targeted sequencing approach. We identified the variant in 66/2634 (2.5%) cases and 33/1996 (1.65%) controls, indicating an enrichment in the breast cancer cases (p = 0.047, OR 1.53, 95% CI 1.00–2.34). This data is consistent with recent iCOGs data suggesting that this variant is not neutral with respect to breast cancer risk. rs11571833 may need to be included in SNP panels for evaluating breast cancer risk. PMID:26455428

  17. Breast cancer in BRCA mutation carriers: medical treatment.

    PubMed

    Milani, Andrea; Geuna, Elena; Zucchini, Giorgia; Aversa, Caterina; Martinello, Rossella; Montemurro, Filippo

    2016-10-01

    About 10% of breast cancers are associated with the inheritance of autosomal dominant breast cancer susceptibility alleles BRCA1 and BRCA2. Until recently, the medical management of BRCA mutation-associated breast cancer has not differed from that of the sporadic breast cancer counterpart. However, there is mounting evidence that this molecular alteration confers sensitivity or resistance to systemic therapies that can be exploited in terms of medical management. For example, studies support the use of platinum salts chemotherapy in BRCA mutated cancers. Moreover, a number of targeted therapies are showing activity in BRCA mutation carriers. Above all, BRCA defective tumor cells are particularly sensitive to Poly(ADP-ribose) polymerase (PARP) inhibitors. This review will summarize the state of the art of the medical treatment of breast cancer in BRCA mutation carriers, with a particular focus on chemotherapies and targeted therapies.

  18. Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites

    PubMed Central

    Rapakko, K; Allinen, M; Syrjäkoski, K; Vahteristo, P; Huusko, P; Vähäkangas, K; Eerola, H; Kainu, T; Kallioniemi, O-P; Nevanlinna, H; Winqvist, R

    2001-01-01

    We have screened for germline TP53 mutations in Finnish BRCA1 and BRCA2 mutation-negative families. This study represents the largest survey of the entire protein-encoding portion of TP53, and indicates that mutations are only found at conserved domains in breast cancer families also meeting the criteria for Li-Fraumeni/Li-Fraumeni-like syndrome, explaining only a very small additional fraction of the hereditary breast cancer cases. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11139324

  19. Inherited Mutations in 17 Breast Cancer Susceptibility Genes Among a Large Triple-Negative Breast Cancer Cohort Unselected for Family History of Breast Cancer

    PubMed Central

    Couch, Fergus J.; Hart, Steven N.; Sharma, Priyanka; Toland, Amanda Ewart; Wang, Xianshu; Miron, Penelope; Olson, Janet E.; Godwin, Andrew K.; Pankratz, V. Shane; Olswold, Curtis; Slettedahl, Seth; Hallberg, Emily; Guidugli, Lucia; Davila, Jaime I.; Beckmann, Matthias W.; Janni, Wolfgang; Rack, Brigitte; Ekici, Arif B.; Slamon, Dennis J.; Konstantopoulou, Irene; Fostira, Florentia; Vratimos, Athanassios; Fountzilas, George; Pelttari, Liisa M.; Tapper, William J.; Durcan, Lorraine; Cross, Simon S.; Pilarski, Robert; Shapiro, Charles L.; Klemp, Jennifer; Yao, Song; Garber, Judy; Cox, Angela; Brauch, Hiltrud; Ambrosone, Christine; Nevanlinna, Heli; Yannoukakos, Drakoulis; Slager, Susan L.; Vachon, Celine M.; Eccles, Diana M.; Fasching, Peter A.

    2015-01-01

    Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives. PMID:25452441

  20. Screening for Novel Germline Rare Mutations Associated with Aggressive Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    Schmidt S., Peshkin L., et al. A method and server for predicting damaging missense mutations. Nat Methods. 7, 248-249 (2010). Akbari MR, Trachtenberg...Inst. 2012 Aug 1;104(16):1260-2. Epub 2012 Jul 9. Castro E. G.C.L., Olmos D., et al. Correlation of germ-line BRCA2 mutations with aggressive...prostate cancer. Clin Cancer Res. 16, 2115-2121 (2010). 20    Hammer GE, Gonzalez F, Champsaur M, Cado D, Shastri N. The aminopeptidase ERAAP shapes the

  1. Cumulative BRCA mutation analysis in the Greek population confirms that homogenous ethnic background facilitates genetic testing.

    PubMed

    Tsigginou, Alexandra; Vlachopoulos, Fotios; Arzimanoglou, Iordanis; Zagouri, Flora; Dimitrakakis, Constantine

    2015-01-01

    Screening for BRCA 1 and BRCA 2 mutations has long moved from the research lab to the clinic as a routine clinical genetic testing. BRCA molecular alteration pattern varies among ethnic groups which makes it already a less straightforward process to select the appropriate mutations for routine genetic testing on the basis of known clinical significance. The present report comprises an in depth literature review of the so far reported BRCA 1 and BRCA 2 molecular alterations in Greek families. Our analysis of Greek cumulative BRCA 1 and 2 molecular data, produced by several independent groups, confirmed that six recurrent deleterious mutations account for almost 60 % and 70 % of all BRCA 1 and 2 and BRCA 1 mutations, respectively. As a result, it makes more sense to perform BRCA mutation analysis in the clinic in two sequential steps, first conventional analysis for the six most prevalent pathogenic mutations and if none identified, a second step of New Generation Sequencing-based whole genome or whole exome sequencing would follow. Our suggested approach would enable more clinically meaningful, considerably easier and less expensive BRCA analysis in the Greek population which is considered homogenous.

  2. Novel germline PALB2 truncating mutations in African-American breast cancer patients

    PubMed Central

    Zheng, Yonglan; Zhang, Jing; Niu, Qun; Huo, Dezheng; Olopade, Olufunmilayo I.

    2011-01-01

    Background It has been demonstrated that PALB2 acts as a bridging molecule between the BRCA1 and BRCA2 proteins and is responsible for facilitating BRCA2-mediated DNA repair. Truncating mutations in the PALB2 gene have been reported to be enriched in Fanconi anemia and breast cancer patients in various populations. Methods We evaluated the contribution of PALB2 germline mutations in 279 African-American breast cancer patients including 29 patients with a strong family history, 29 patients with a moderate family history, 75 patients with a weak family history, and 146 non-familial or sporadic breast cancer cases. Results After direct sequencing of all the coding exons, exon/intron boundaries, 5′UTR and 3′UTR of PALB2, three (1.08%; 3 in 279) novel monoallelic truncating mutations were identified: c.758dupT (exon4), c.1479delC (exon4) and c.3048delT (exon 10); together with 50 sequence variants, 27 of which are novel. None of the truncating mutations were found in 262 controls from the same population. Conclusions PALB2 mutations are present in both familial and non-familial breast cancer among African-Americans. Rare PALB2 mutations account for a small but substantial proportion of breast cancer patients. PMID:21932393

  3. Frequent incidence of BARD1-truncating mutations in germline DNA from triple-negative breast cancer patients.

    PubMed

    De Brakeleer, S; De Grève, J; Desmedt, C; Joris, S; Sotiriou, C; Piccart, M; Pauwels, I; Teugels, E

    2016-03-01

    Triple-negative breast cancer (TNBC) accounts for 10-20% of all breast cancers (BCs), and conventional chemotherapy is the only effective systemic treatment. Germline BRCA1/2 mutations are found in approximately 15% of TNBC patients. In the past, we have documented pathogenic mutations in BARD1, a BRCA1 interacting protein, in families at high risk for BC. In this study, we have analyzed germline DNA from 61 estrogen receptor negative patients (of which 42 were TNBC) for the presence of mutations in the BRCA1, BRCA2 and BARD1 gene. BRCA1/2 mutations were found in 8 out of 42 (19%) TNBC patients, but not in the ER-/HER2+ cohort. We also found four good candidate pathogenic BARD1 mutations in the TNBC cohort, including two protein-truncating mutations (p.Gln564Ter and p.Arg641Ter). Our data suggest that TNBC patients are enriched for pathogenic BARD1 germline mutations as compared to control samples and high BC risk families. Ten of the 42 investigated TNBC patients carry a BRCA pathway mutation (in BRCA1, BRCA2 or BARD1) rendering them susceptible to homologous recombination deficiency. These patients should become eligible for exploring the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors.

  4. Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

    PubMed Central

    Jakubowska, A; Rozkrut, D; Antoniou, A; Hamann, U; Scott, R J; McGuffog, L; Healy, S; Sinilnikova, O M; Rennert, G; Lejbkowicz, F; Flugelman, A; Andrulis, I L; Glendon, G; Ozcelik, H; Thomassen, M; Paligo, M; Aretini, P; Kantala, J; Aroer, B; von Wachenfeldt, A; Liljegren, A; Loman, N; Herbst, K; Kristoffersson, U; Rosenquist, R; Karlsson, P; Stenmark-Askmalm, M; Melin, B; Nathanson, K L; Domchek, S M; Byrski, T; Huzarski, T; Gronwald, J; Menkiszak, J; Cybulski, C; Serrano, P; Osorio, A; Cajal, T R; Tsitlaidou, M; Benítez, J; Gilbert, M; Rookus, M; Aalfs, C M; Kluijt, I; Boessenkool-Pape, J L; Meijers-Heijboer, H E J; Oosterwijk, J C; van Asperen, C J; Blok, M J; Nelen, M R; van den Ouweland, A M W; Seynaeve, C; van der Luijt, R B; Devilee, P; Easton, D F; Peock, S; Frost, D; Platte, R; Ellis, S D; Fineberg, E; Evans, D G; Lalloo, F; Eeles, R; Jacobs, C; Adlard, J; Davidson, R; Eccles, D; Cole, T; Cook, J; Godwin, A; Bove, B; Stoppa-Lyonnet, D; Caux-Moncoutier, V; Belotti, M; Tirapo, C; Mazoyer, S; Barjhoux, L; Boutry-Kryza, N; Pujol, P; Coupier, I; Peyrat, J-P; Vennin, P; Muller, D; Fricker, J-P; Venat-Bouvet, L; Johannsson, O Th; Isaacs, C; Schmutzler, R; Wappenschmidt, B; Meindl, A; Arnold, N; Varon-Mateeva, R; Niederacher, D; Sutter, C; Deissler, H; Preisler-Adams, S; Simard, J; Soucy, P; Durocher, F; Chenevix-Trench, G; Beesley, J; Chen, X; Rebbeck, T; Couch, F; Wang, X; Lindor, N; Fredericksen, Z; Pankratz, V S; Peterlongo, P; Bonanni, B; Fortuzzi, S; Peissel, B; Szabo, C; Mai, P L; Loud, J T; Lubinski, J

    2012-01-01

    Background: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. Methods: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. Results: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10–2.04 and HR 2.16, 95%CI 1.24–3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. Conclusion: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. PMID:22669161

  5. Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy.

    PubMed

    Schmidt, Hartmut H-J; Barroso, Fabio; González-Duarte, Alejandra; Conceição, Isabel; Obici, Laura; Keohane, Denis; Amass, Leslie

    2016-09-01

    Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, severe, and irreversible, adult-onset, hereditary disorder caused by autosomal-dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR-FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease-modifying treatment options for a wider spectrum of patients with TTR-FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation-specific predictive genetic testing in first-degree relatives of index patients diagnosed with TTR-FAP and the structured clinical follow-up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353-360, 2016.

  6. Antimicrobial Treatment of Asymptomatic Bacteriuria in Healthy Ambulatory Subjects.

    ERIC Educational Resources Information Center

    Zhanel, George G.

    1990-01-01

    The treatment of urinary tract infections is discussed. Specific issues considered include the definition of asymptomatic bacteriuria, the prevalence of asymptomatic bacteriuria, the controversies of who should be treated, and antimicrobial treatment of asymptomatic bacteriuria. (MLW)

  7. Molecular analysis of hepatitis B virus "a" determinant in asymptomatic and symptomatic Mexican carriers

    PubMed Central

    Ruiz-Tachiquín, Martha-Eugenia; Valdez-Salazar, Hilda-Alicia; Juárez-Barreto, Vicencio; Dehesa-Violante, Margarita; Torres, Javier; Muñoz-Hernández, Onofre; Alvarez-Muñoz, Ma-Teresa

    2007-01-01

    Background Hepatitis B virus (HBV) is a small DNA-containing virus with 4 genes, C, S, X and P. The S gene codes for the surface antigen (HBsAg), which contains the "a" determinant, the main region for induction of a protective humoral immune response. To compare the genotype and sequence of the "a" determinant between strains isolated from asymptomatic and symptomatic Mexican HBV carriers. Results 21 asymptomatic (blood donors) and 12 symptomatic (with clinical signs and with >1 year lamivudine treatment) HBV carriers were studied; all patients were positive for the HBsAg in serum. Viral load, genotypes, and subtypes were determined in plasma. A fragment of the S gene including the "a" determinant was PCR amplified and sequenced to determine genotype, subtype and to identify mutations. Mean viral load was 0.7965 × 104 copies/ml in asymptomatic carriers and 2.73 × 106 copies/ml in symptomatic patients. Genotypes H, C, and F were identified in asymptomatic individuals; whereas H was dominant in symptomatic patients. A fragment of 279 bp containing the "a" determinant was amplified from all 33 carriers and sequences aligned with S gene sequences in the GenBank. Mutations identified were Y100N, T126I, Q129H and N146K in the asymptomatic group, and F93I and A128V in the symptomatic group. Conclusion Differences in genotype and in mutations in the "a" determinant were found between strains from asymptomatic and symptomatic HBV Mexican carriers. PMID:17217533

  8. Gallstone ileus in an 'asymptomatic' parastomal hernia.

    PubMed

    Jayamanne, H; Brown, J; Stephenson, B M

    2016-09-01

    Parastomal hernias are common and often asymptomatic. We report the first known case in which later, acute symptoms developed owing to gallstone ileus in a sac containing both omentum and small bowel. Urgent computed tomography established the diagnosis.

  9. Biochemical Characterization of BRCA2

    DTIC Science & Technology

    2004-04-01

    2000. DNA replication is required to elicit cellular responses to psoralen -induced DNA interstrand crosslinks. Mol. Cell. Biol. 20:8283-8289 13. de...breaks by psoralen DNA interstrand cross-links. 2003. J. Biol. Chem. 278:5250-4. 15. Rothfuss, A, and Grompe, M. Repair kinetics of genomic interstrand

  10. Detection of a novel mutation in exon 20 of the BRCA1 gene.

    PubMed

    Chakraborty, Abhijit; Katarkar, Atul; Chaudhuri, Keya; Mukhopadhyay, Ashis; Basak, Jayasri

    2013-12-01

    Hereditary breast cancer constitutes 5-10% of all breast cancer cases. Inherited mutations in the BRCA1 and BRCA2 tumor-suppressor genes account for the majority of hereditary breast cancer cases. The BRCA1 C-terminal region (BRCT) has a functional duplicated globular domain, which helps with DNA damage repair and cell cycle checkpoint protein control. More than 100 distinct BRCA1 missense variants with structural and functional effects have been documented within the BRCT domain. Interpreting the results of mutation screening of tumor-suppressor genes that can have high-risk susceptibility mutations is increasingly important in clinical practice. This study includes a novel mutation, p.His1746 Pro (c.5237A>C), which was found in BRCA1 exon 20 of a breast cancer patient. In silico analysis suggests that this mutation could alter the stability and orientation of the BRCT domain and the differential binding of the BACH1 substrate.

  11. Asymptomatic Norovirus Infection in Mexican Children

    PubMed Central

    García, Coralith; DuPont, Herbert L.; Long, Kurt Z.; Santos, Jose I.; Ko, GwangPyo

    2006-01-01

    Sixty-three children in periurban Mexico City were examined for the occurrence of asymptomatic norovirus (NoV) infection from June to August 1998. NoV was detected in 48 of 161 stool specimens (29.8%), with 31 children (49.2%) having at least one positive stool. Asymptomatic NoV infection occurred commonly during summertime in a Mexican pediatric population. PMID:16891526

  12. Carcinoid Tumor in Accidental, Asymptomatic Meckel's Diverticulum.

    PubMed

    Baranyai, Zsolt; Jósa, Valeria; Merkel, Keresztely; Zolnai, Zsofia

    2013-01-01

    Although Meckel's diverticulum is the most common congenital gastrointestinal disorder, it is controversial whether asymptomatic diverticula in adults should be respected. The authors report the case of a patient who was operated due to ileus caused by adhesions and a Meckel's diverticulum without any sign of inflammation was accidentally noted and removed. As a surprise, the pathological examination of the diverticulum proved carcinoid tumor, a neuroendocrine malignant tumor. The case raises the importance of the removal of asymptomatic Meckel's diverticulum.

  13. Carcinoid Tumor in Accidental, Asymptomatic Meckel's Diverticulum

    PubMed Central

    Baranyai, Zsolt; Jósa, Valeria; Merkel, Keresztely; Zolnai, Zsofia

    2013-01-01

    Although Meckel's diverticulum is the most common congenital gastrointestinal disorder, it is controversial whether asymptomatic diverticula in adults should be respected. The authors report the case of a patient who was operated due to ileus caused by adhesions and a Meckel's diverticulum without any sign of inflammation was accidentally noted and removed. As a surprise, the pathological examination of the diverticulum proved carcinoid tumor, a neuroendocrine malignant tumor. The case raises the importance of the removal of asymptomatic Meckel's diverticulum. PMID:24470856

  14. β-HPV 5 and 8 E6 Disrupt Homology Dependent Double Strand Break Repair by Attenuating BRCA1 and BRCA2 Expression and Foci Formation

    PubMed Central

    Wallace, Nicholas A.; Robinson, Kristin; Howie, Heather L.; Galloway, Denise A.

    2015-01-01

    Recent work has explored a putative role for the E6 protein from some β-human papillomavirus genus (β-HPVs) in the development of non-melanoma skin cancers, specifically β-HPV 5 and 8 E6. Because these viruses are not required for tumor maintenance, they are hypothesized to act as co-factors that enhance the mutagenic capacity of UV-exposure by disrupting the repair of the resulting DNA damage. Supporting this proposal, we have previously demonstrated that UV damage signaling is hindered by β-HPV 5 and 8 E6 resulting in an increase in both thymine dimers and UV-induced double strand breaks (DSBs). Here we show that β-HPV 5 and 8 E6 further disrupt the repair of these DSBs and provide a mechanism for this attenuation. By binding and destabilizing a histone acetyltransferase, p300, β-HPV 5 and 8 E6 reduce the enrichment of the transcription factor at the promoter of two genes critical to the homology dependent repair of DSBs (BRCA1 and BRCA2). The resulting diminished BRCA1/2 transcription not only leads to lower protein levels but also curtails the ability of these proteins to form repair foci at DSBs. Using a GFP-based reporter, we confirm that this reduced foci formation leads to significantly diminished homology dependent repair of DSBs. By deleting the p300 binding domain of β-HPV 8 E6, we demonstrate that the loss of robust repair is dependent on viral-mediated degradation of p300 and confirm this observation using a combination of p300 mutants that are β-HPV 8 E6 destabilization resistant and p300 knock-out cells. In conclusion, this work establishes an expanded ability of β-HPV 5 and 8 E6 to attenuate UV damage repair, thus adding further support to the hypothesis that β-HPV infections play a role in skin cancer development by increasing the oncogenic potential of UV exposure. PMID:25803638

  15. A High Frequency of BRCA Mutations in Young Black Women with Breast Cancer from Florida

    PubMed Central

    Pal, Tuya; Bonner, Devon; Cragun, Deborah; Monteiro, Alvaro N.A.; Phelan, Catherine; Servais, Lily; Kim, Jongphil; Narod, Steven A.; Akbari, Mohammad R.; Vadaparampil, Susan

    2015-01-01

    PURPOSE Black women are disproportionately affected with triple negative breast cancer and have relatively poor survival. It is not known to what extent differences in clinical presentation of breast cancer in Non-Hispanic White (NHW) women and Black women can be accounted for by the presence of mutations in the BRCA1 and BRCA2 (BRCA) genes. We sought to evaluate the frequency of BRCA pathogenic variants in a population-based sample of young Black women with breast cancer. PATIENTS AND METHODS Black women diagnosed with invasive breast cancer at or before age 50 from 2009 to 2012 were recruited to the study through the Florida Cancer Registry. Participants underwent genetic counseling, completed a study questionnaire and consented to release of their medical records. Saliva specimens were collected for BRCA sequencing and large rearrangement testing through MLPA. RESULTS A DNA sample was evaluated for 396 women of whom 49 (12.4%) had a mutation in BRCA1 or BRCA2. Eight recurrent mutations accounted for 49% of all pathogenic variants. CONCLUSIONS The prevalence of BRCA mutations among our Florida-based sample of young Black women with breast cancer exceeds that previously reported for NHW women. It is appropriate to recommend BRCA testing in all young Black women with invasive breast cancer. PMID:26287763

  16. Germline BRCA Mutations Are Associated With Higher Risk of Nodal Involvement, Distant Metastasis, and Poor Survival Outcomes in Prostate Cancer

    PubMed Central

    Castro, Elena; Goh, Chee; Olmos, David; Saunders, Ed; Leongamornlert, Daniel; Tymrakiewicz, Malgorzata; Mahmud, Nadiya; Dadaev, Tokhir; Govindasami, Koveela; Guy, Michelle; Sawyer, Emma; Wilkinson, Rosemary; Ardern-Jones, Audrey; Ellis, Steve; Frost, Debra; Peock, Susan; Evans, D. Gareth; Tischkowitz, Marc; Cole, Trevor; Davidson, Rosemarie; Eccles, Diana; Brewer, Carole; Douglas, Fiona; Porteous, Mary E.; Donaldson, Alan; Dorkins, Huw; Izatt, Louise; Cook, Jackie; Hodgson, Shirley; Kennedy, M. John; Side, Lucy E.; Eason, Jacqueline; Murray, Alex; Antoniou, Antonis C.; Easton, Douglas F.; Kote-Jarai, Zsofia; Eeles, Rosalind

    2013-01-01

    Purpose To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes. Patients and Methods This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1). Results PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup. Conclusion Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients. PMID:23569316

  17. Peripheral immunophenotype and viral promoter variants during the asymptomatic phase of feline immunodeficiency virus infection

    PubMed Central

    Murphy, B.; Hillman, C.; McDonnel, S.

    2014-01-01

    Feline immunodeficiency virus (FIV)-infected cats enter a clinically asymptomatic phase during chronic infection. Despite the lack of overt clinical disease, the asymptomatic phase is characterized by persistent immunologic impairment. In the peripheral blood obtained from cats experimentally infected with FIV-C for approximately 5 years, we identified a persistent inversion of the CD4/CD8 ratio. We cloned and sequenced the FIV-C long terminal repeat containing the viral promoter from cells infected with the inoculating virus and from in vivo-derived peripheral blood mononuclear cells and CD4 T cells isolated at multiple time points throughout the asymptomatic phase. Relative to the inoculating virus, viral sequences amplified from cells isolated from all of the infected animals demonstrated multiple single nucleotide mutations and a short deletion within the viral U3, R and U5 regions. A transcriptionally inactivating proviral mutation in the U3 promoter AP-1 site was identified at multiple time points from all of the infected animals but not within cell-associated viral RNA. In contrast, no mutations were identified within the sequence of the viral dUTPase gene amplified from PBMC isolated at approximately 5 years post-infection relative to the inoculating sequence. The possible implications of these mutations to viral pathogenesis are discussed. PMID:24291288

  18. BRCC3 mutations in myeloid neoplasms

    PubMed Central

    Huang, Dayong; Nagata, Yasunobu; Grossmann, Vera; Radivoyevitch, Tomas; Okuno, Yusuke; Nagae, Genta; Hosono, Naoko; Schnittger, Susanne; Sanada, Masashi; Przychodzen, Bartlomiej; Kon, Ayana; Polprasert, Chantana; Shen, Wenyi; Clemente, Michael J.; Phillips, James G.; Alpermann, Tamara; Yoshida, Kenichi; Nadarajah, Niroshan; Sekeres, Mikkael A.; Oakley, Kevin; Nguyen, Nhu; Shiraishi, Yuichi; Shiozawa, Yusuke; Chiba, Kenichi; Tanaka, Hiroko; Koeffler, H. Phillip; Klein, Hans-Ulrich; Dugas, Martin; Aburatani, Hiroyuki; Miyano, Satoru; Haferlach, Claudia; Kern, Wolfgang; Haferlach, Torsten; Du, Yang; Ogawa, Seishi; Makishima, Hideki

    2015-01-01

    Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84–4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25–11.0). Clinically, BRCC3 mutations were also related to higher age (P=0.01), although prognosis was not affected. Knockdown of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. PMID:26001790

  19. Retinal Ganglion Cell Dysfunction in Asymptomatic G11778A: Leber Hereditary Optic Neuropathy

    PubMed Central

    Guy, John; Feuer, William J.; Porciatti, Vittorio; Schiffman, Joyce; Abukhalil, Fawzi; Vandenbroucke, Ruth; Rosa, Potyra R.; Lam, Byron L.

    2014-01-01

    Purpose. To report the serial evaluation of asymptomatic eyes of subjects with mutated G11778A mitochondrial DNA. Methods. Forty-five asymptomatic G11778A Leber hereditary optic neuropathy (LHON) carriers and two patients with the mutation who developed unilateral visual loss underwent testing that included visual acuity, automated visual field, pattern electroretinogram (PERG), and spectral-domain optical coherence tomography every 6 months between September 2008 and March 2012. Results. Visual acuity, visual fields, and retinal nerve fiber layer thickness remained stable within the normal range. Mean PERG amplitudes of carriers dropped progressively by ∼40% from baseline to 36 months. In addition, comparisons with the fellow eyes of patients with unilateral optic neuritis revealed a 3.4 ETDRS (Early Treatment Diabetic Retinopathy Study) letter loss in the LHON carriers. A single carrier developed visual loss, with PERG amplitudes dropping by half. In one of two LHON cases who presented with unilateral visual loss, visual acuity in the asymptomatic eye was ∼20/40 at baseline. The PERG amplitude of this eye was reduced to ∼30% of normal. Six months later, his visual acuity had dropped to ∼20/500. A second patient who was ∼20/20 and had a visual field defect in the asymptomatic eye at baseline remained at this level for the 18 months of follow-up. His PERG amplitudes were similar to those of asymptomatic carriers, with 0.78 μV at baseline that did not decline with follow-up. Conclusions. Declines of the PERG amplitude suggest subclinical retinal ganglion cell dysfunction in asymptomatic G11778A subjects, which is progressive. PMID:24398093

  20. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.

    PubMed Central

    Friedman, L S; Szabo, C I; Ostermeyer, E A; Dowd, P; Butler, L; Park, T; Lee, M K; Goode, E L; Rowell, S E; King, M C

    1995-01-01

    Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset breast cancer without ovarian cancer. Mutation 4184delTCAA occurred independently in two families. In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years. Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer. A 665-nt segment of the BRCA1 3'-UTR and 1.3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations. Overall in our series, BRCA1 mutations have been detected in 26 families: 16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2. Images Figure 5 PMID:8533757

  1. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families

    SciTech Connect

    Friedman, L.S.; Szabo, C.I.; Ostermeyer, E.A.

    1995-12-01

    Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning {approximately}850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset bilateral breast cancer and ovarian cancer to late-onset breast cancer without ovarian cancer. Mutation 4184delTCAA occurred independently in two families. In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years. Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer. A 665-nt segment of the BRCA1 3{prime}-UTR and 1.3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations. Overall in our series, BRCA1 mutations have been detected in 26 families: 16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2. 57 refs., 5 figs., 3 tabs.

  2. ENIGMA--evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes.

    PubMed

    Spurdle, Amanda B; Healey, Sue; Devereau, Andrew; Hogervorst, Frans B L; Monteiro, Alvaro N A; Nathanson, Katherine L; Radice, Paolo; Stoppa-Lyonnet, Dominique; Tavtigian, Sean; Wappenschmidt, Barbara; Couch, Fergus J; Goldgar, David E

    2012-01-01

    As genetic testing for predisposition to human diseases has become an increasingly common practice in medicine, the need for clear interpretation of the test results is apparent. However, for many disease genes, including the breast cancer susceptibility genes BRCA1 and BRCA2, a significant fraction of tests results in the detection of a genetic variant for which disease association is not known. The finding of an "unclassified" variant (UV)/variant of uncertain significance (VUS) complicates genetic test reporting and counseling. As these variants are individually rare, a large collaboration of researchers and clinicians will facilitate studies to assess their association with cancer predisposition. It was with this in mind that the ENIGMA consortium (www.enigmaconsortium.org) was initiated in 2009. The membership is both international and interdisciplinary, and currently includes more than 100 research scientists and clinicians from 19 countries. Within ENIGMA, there are presently six working groups focused on the following topics: analysis, clinical, database, functional, tumor histopathology, and mRNA splicing. ENIGMA provides a mechanism to pool resources, exchange methods and data, and coordinately develop and apply algorithms for classification of variants in BRCA1 and BRCA2. It is envisaged that the research and clinical application of models developed by ENIGMA will be relevant to the interpretation of sequence variants in other disease genes.

  3. Mutational Processes Molding the Genomes of 21 Breast Cancers

    PubMed Central

    Nik-Zainal, Serena; Alexandrov, Ludmil B.; Wedge, David C.; Van Loo, Peter; Greenman, Christopher D.; Raine, Keiran; Jones, David; Hinton, Jonathan; Marshall, John; Stebbings, Lucy A.; Menzies, Andrew; Martin, Sancha; Leung, Kenric; Chen, Lina; Leroy, Catherine; Ramakrishna, Manasa; Rance, Richard; Lau, King Wai; Mudie, Laura J.; Varela, Ignacio; McBride, David J.; Bignell, Graham R.; Cooke, Susanna L.; Shlien, Adam; Gamble, John; Whitmore, Ian; Maddison, Mark; Tarpey, Patrick S.; Davies, Helen R.; Papaemmanuil, Elli; Stephens, Philip J.; McLaren, Stuart; Butler, Adam P.; Teague, Jon W.; Jönsson, Göran; Garber, Judy E.; Silver, Daniel; Miron, Penelope; Fatima, Aquila; Boyault, Sandrine; Langerød, Anita; Tutt, Andrew; Martens, John W.M.; Aparicio, Samuel A.J.R.; Borg, Åke; Salomon, Anne Vincent; Thomas, Gilles; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Neuberger, Michael S.; Futreal, P. Andrew; Campbell, Peter J.; Stratton, Michael R.

    2012-01-01

    Summary All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed “kataegis,” was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed. PaperClip PMID:22608084

  4. High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

    PubMed Central

    Pölsler, Laura; Fiegl, Heidi; Wimmer, Katharina; Oberaigner, Willi; Amberger, Albert; Traunfellner, Pia; Morscher, Raphael J; Weber, Ingrid; Fauth, Christine; Wernstedt, Annekatrin; Sperner-Unterweger, Barbara; Oberguggenberger, Anne; Hubalek, Michael; Marth, Christian; Zschocke, Johannes

    2016-01-01

    Screening for founder mutations in BRCA1 and BRCA2 has been discussed as a cost-effective testing strategy in certain populations. In this study, comprehensive BRCA1 and BRCA2 testing was performed in a routine diagnostic setting. The prevalence of the BRCA1 stop mutation c.4183C>T, p.(Gln1395Ter), was determined in unselected breast and ovarian cancer patients from different regions in the Tyrol. Cancer registry data were used to evaluate the impact of this mutation on regional cancer incidence. The mutation c.4183C>T was detected in 30.4% of hereditary BRCA1-associated breast and ovarian cancer patients in our cohort. It was also identified in 4.1% of unselected (26% of unselected triple negative) Tyrolean breast cancer patients and 6.8% of unselected ovarian cancer patients from the Lower Inn Valley (LIV) region. Cancer incidences showed a region-specific increase in age-stratified breast and ovarian cancer risk with standardized incidence ratios of 1.23 and 2.13, respectively. We, thus, report a Tyrolean BRCA1 founder mutation that correlates to a local increase in the breast and ovarian cancer risks. On the basis of its high prevalence, we suggest that targeted genetic analysis should be offered to all women with breast or ovarian cancer and ancestry from the LIV region. PMID:26014432

  5. Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy

    PubMed Central

    Barroso, Fabio; González‐Duarte, Alejandra; Conceição, Isabel; Obici, Laura; Keohane, Denis; Amass, Leslie

    2016-01-01

    ABSTRACT Transthyretin familial amyloid polyneuropathy (TTR‐FAP) is a rare, severe, and irreversible, adult‐onset, hereditary disorder caused by autosomal‐dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR‐FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease‐modifying treatment options for a wider spectrum of patients with TTR‐FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation‐specific predictive genetic testing in first‐degree relatives of index patients diagnosed with TTR‐FAP and the structured clinical follow‐up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353–360, 2016 PMID:27273296

  6. Experience with Bilateral Risk-Reducing Mastectomy for an Unaffected BRCA Mutation Carrier

    PubMed Central

    Maeshima, Yurina; Oseto, Kumiko; Katsuragi, Ryohei; Yoshimoto, Yukiko; Takahara, Sachiko

    2016-01-01

    Women with BRCA1/2 mutations have a high risk of breast cancer and may opt for risk-reducing mastectomy (RRM). We report a 38-year-old Japanese woman who was diagnosed as a BRCA2 mutation carrier. She underwent prophylactic bilateral skin-sparing mastectomy (SSM) with excision of the nipple and preservation of the areola skin. It is unclear whether a bilateral RRM leads to better survival compared with intensive surveillance. The oncological risk associated with the presence of remnant breast glandular tissue after SSM or nipple-sparing mastectomy has been obscure. We report the first case of RRM for a Japanese BRCA mutation carrier and provide a literature review on risk management for BRCA mutation carriers with a focus on the concepts and procedures of RRM. PMID:27382401

  7. The prevalence of BRCA mutations among familial breast cancer patients in Korea: results of the Korean Hereditary Breast Cancer study.

    PubMed

    Han, Sang-Ah; Kim, Sung-Won; Kang, Eunyoung; Park, Sue K; Ahn, Sei-Hyun; Lee, Min Hyuk; Nam, Seok-Jin; Han, Wonshik; Bae, Young Tae; Kim, Hyun-Ah; Cho, Young Up; Chang, Myung Chul; Paik, Nam Sun; Hwang, Ki-Tae; Kim, Sei Joong; Noh, Dong-Young; Choi, Doo Ho; Noh, Woo-Chul; Kim, Lee Su; Kim, Ku Sang; Suh, Young Jin; Lee, Jeong Eon; Jung, Yongsik; Moon, Byung-In; Yang, Jung-Hyun; Son, Byung Ho; Yom, Cha Kyong; Kim, Sung Yong; Lee, Hyde; Jung, Sung Hoo

    2013-03-01

    The primary aim of this study was to estimate the prevalence of BRCA1/2 mutations among familial breast cancer (BC) patients in Korea. We analyzed 775 familial BC patients who were enrolled in the Korean Hereditary Breast Cancer (KOHBRA) study and treated at 36 institutions between May 2007 and May 2010. Patients with familial BC were defined as BC patients with family histories of BC or ovarian cancer (OC) in any relatives. All probands received genetic counseling and BRCA genetic testing was performed after obtaining informed consent. The mean age of BC diagnosis was 43.6 years. The numbers of probands with family histories of BC only and OC only were 682 and 93, respectively. The overall prevalence of the BRCA mutation among familial BC patients was 21.7 % (BRCA1 9.3 % and BRCA2 12.4 %). Subgroup analyses observed prevalences of the BRCA mutation as follows: 19.6 % among patients with BC family history only (BRCA1 7.6 % and BRCA2 12.0 %) and 36.6 % among patients with OC family history only (BRCA1 21.5 % and BRCA2 15.1 %). Most of the subgroups satisfied the 10 % probability criteria to undergo BRCA testing. However, the prevalence of the BRCA mutations among subgroups that had 2 BC patients in a family with both age at diagnosis of more than 50 years old did not reach the 10 % criteria (4.1 %). Korean familial BC patients are good candidates for BRCA testing even when they have family histories of single breast cancers. However, proband age at diagnosis should be carefully considered when selecting patients for testing.

  8. Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations.

    PubMed

    Caminsky, Natasha G; Mucaki, Eliseos J; Perri, Ami M; Lu, Ruipeng; Knoll, Joan H M; Rogan, Peter K

    2016-07-01

    BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer (HBOC) does not identify all pathogenic variants. Sequencing of 20 complete genes in HBOC patients with uninformative test results (N = 287), including noncoding and flanking sequences of ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51B, STK11, TP53, and XRCC2, identified 38,372 unique variants. We apply information theory (IT) to predict and prioritize noncoding variants of uncertain significance in regulatory, coding, and intronic regions based on changes in binding sites in these genes. Besides mRNA splicing, IT provides a common framework to evaluate potential affinity changes in transcription factor (TFBSs), splicing regulatory (SRBSs), and RNA-binding protein (RBBSs) binding sites following mutation. We prioritized variants affecting the strengths of 10 splice sites (four natural, six cryptic), 148 SRBS, 36 TFBS, and 31 RBBS. Three variants were also prioritized based on their predicted effects on mRNA secondary (2°) structure and 17 for pseudoexon activation. Additionally, four frameshift, two in-frame deletions, and five stop-gain mutations were identified. When combined with pedigree information, complete gene sequence analysis can focus attention on a limited set of variants in a wide spectrum of functional mutation types for downstream functional and co-segregation analysis.

  9. Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington's disease.

    PubMed

    Antonini, A; Leenders, K L; Spiegel, R; Meier, D; Vontobel, P; Weigell-Weber, M; Sanchez-Pernaute, R; de Yébenez, J G; Boesiger, P; Weindl, A; Maguire, R P

    1996-12-01

    We used PET scans with the tracers [18F]fluorodeoxyglucose (FDG) and [11C]raclopride (RACLO) to study glucose metabolism and dopamine D2 receptor binding in the caudate nucleus and putamen of 18 carriers of the Huntington's disease gene mutation (10 asymptomatic subjects and eight untreated symptomatic Huntington's disease patients in an early disease stage). We also performed MRI scans and measured the bicaudate ratio (BCR) in the same subjects. Data were compared with those from nine mutation-negative members of Huntington's disease families and separate groups of age matched controls. The PET scans were repeated 1.5-3 years later in six of the asymptomatic gene carriers. Symptomatic Huntington's disease patients showed a marked reduction of FDG and RACLO uptake in the caudate nucleus and putamen and a significant increase of BCR. Asymptomatic mutation carriers revealed significant hypometabolism in the caudate nucleus and putamen. The RACLO binding was significantly decreased in the putamen. Decrements of caudate nucleus tracer uptake, particularly RACLO, correlated significantly with BCR increases in both symptomatic and asymptomatic gene carriers. In asymptomatic carriers, metabolic and receptor binding decreases were also significantly associated with the CAG repeat number but not with the individual's age. Discriminant function analysis correctly classified clinical and genetic status in 24 of 27 subjects on the basis of their striatal PET values (83% sensitivity and 100% specificity). Three asymptomatic mutation carriers were classified/grouped together with mutation-negative subjects, indicating that these individuals had normal striatal RACLO and FDG uptake. Follow-up PET data from gene-positive subjects showed a significant reduction in the mean striatal RACLO binding of 6.3% per year. Striatal glucose metabolism revealed an overall non significant 2.3% decrease per year. These data indicate that asymptomatic Huntington's disease mutation carriers may

  10. An Asymptomatic and Overelongated Styloid Process

    PubMed Central

    Altan, Ahmet; Akbulut, Nıhat

    2017-01-01

    Elongation of the styloid process is a rare condition. Only 4% of patients have clinical symptoms where elongated styloid process (ESP) occasionally irritates or disrupts adjacent anatomical structures, which is called Eagle syndrome. This present report was aimed at reporting an asymptomatic ESP with unusual width and length. PMID:28246562

  11. Brief report: Emotional distress and recent stressful life events in long QT syndrome mutation carriers.

    PubMed

    Määttänen, Ilmari; Jokela, Markus; Pulkki-Råback, Laura; Keltikangas-Järvinen, Liisa; Swan, Heikki; Toivonen, Lauri; Merjonen, Päivi; Hintsa, Taina

    2015-11-01

    To study emotional distress in symptomatic and asymptomatic long QT syndrome mutation carriers who had experienced a recent stressful life event. The participants were 209 symptomatic and 279 asymptomatic long QT syndrome mutation carriers. Emotional distress was assessed with the Cope questionnaire and stressful life events with the Social Readjustment Rating Scale. Symptomatic long QT syndrome mutation carriers with burdening recent stressful life events reported a higher emotional distress (β = 0.35, p < 0.001), while the asymptomatic did not show such difference (β = 0.13, p = 0.393). Symptomatic long QT syndrome mutation carriers who have experienced stressful life events recently report an increased emotional distress.

  12. Prognostic significance of BRCA mutations in ovarian cancer: an updated systematic review with meta-analysis

    PubMed Central

    Zhao, Yingchao

    2017-01-01

    There is no consensus on the syntheses concerning the impact of BRCA mutation on ovarian cancer survival. A systematic review and meta-analysis of observational studies was conducted that evaluated the impact of BRCA mutations on the survival outcomes of patients with ovarian cancer. The primary outcome measure was overall survival (OS) and secondary outcome was progression-free survival (PFS). We presented data with hazard ratios (HRs) and 95% confidence interval (CI) and pooled them using the random-effects models. From 2,624 unique records, 34 eligible studies including 18,396 patients were identified. BRCA1/2 mutations demonstrated both OS and PFS benefits in patients with ovarian cancer (OS: HR = 0.67, 95% CI, 0.57 to 0.78, I2 = 76.5%, P <0.001; PFS: HR = 0.62, 95% CI, 0.53 to 0.73, I2 = 18.1%, P = 0.261). For BRCA1 mutation carriers, the HRs for OS and PFS benefits were 0.73 (95% CI, 0.63 to 0.86) and 0.68 (95% CI, 0.52 to 0.89), respectively. For BRCA2 mutation carriers, the HRs for OS and PFS benefits were 0.57 (95% CI, 0.45 to 0.73) and 0.48 (95% CI, 0.30 to 0.75), respectively. The results of subgroup analyses for OS stratified by study quality, tumor stage, study design, sample size, number of research center, duration of follow-up, baseline characteristics adjusted and tumor histology were mostly constant across BRCA1/2, BRCA1 and BRCA2 mutation subtypes. In summary, for patients with ovarian cancer, BRCA mutations were associated with improved OS and PFS. Further large-scale prospective cohort studies should be conducted to test its benefits in specific patients. PMID:27690218

  13. gDNA enrichment by a transposase-based technology for NGS analysis of the whole sequence of BRCA1, BRCA2, and 9 genes involved in DNA damage repair.

    PubMed

    Chevrier, Sandy; Boidot, Romain

    2014-10-06

    The widespread use of Next Generation Sequencing has opened up new avenues for cancer research and diagnosis. NGS will bring huge amounts of new data on cancer, and especially cancer genetics. Current knowledge and future discoveries will make it necessary to study a huge number of genes that could be involved in a genetic predisposition to cancer. In this regard, we developed a Nextera design to study 11 complete genes involved in DNA damage repair. This protocol was developed to safely study 11 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD50, RAD51C, RAD80, and TP53) from promoter to 3'-UTR in 24 patients simultaneously. This protocol, based on transposase technology and gDNA enrichment, gives a great advantage in terms of time for the genetic diagnosis thanks to sample multiplexing. This protocol can be safely used with blood gDNA.

  14. Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing.

    PubMed

    Francke, Uta; Dijamco, Cheri; Kiefer, Amy K; Eriksson, Nicholas; Moiseff, Bianca; Tung, Joyce Y; Mountain, Joanna L

    2013-01-01

    Background. Inherited BRCA gene mutations convey a high risk for breast and ovarian cancer, but current guidelines limit BRCA mutation testing to women with early-onset cancer and relatives of mutation-positive cases. Benefits and risks of providing this information directly to consumers are unknown. Methods. To assess and quantify emotional and behavioral reactions of consumers to their 23andMe Personal Genome Service(®) report of three BRCA mutations that are common in Ashkenazi Jews, we invited all 136 BRCA1 and BRCA2 mutation-positive individuals in the 23andMe customer database who had chosen to view their BRCA reports to participate in this IRB-approved study. We also invited 160 mutation-negative customers who were matched for age, sex and ancestry. Semi-structured phone interviews were completed for 32 mutation carriers, 16 women and 16 men, and 31 non-carriers. Questions addressed personal and family history of cancer, decision and timing of viewing the BRCA report, recollection of the result, emotional responses, perception of personal cancer risk, information sharing, and actions taken or planned. Results. Eleven women and 14 men had received the unexpected result that they are carriers of a BRCA1 185delAG or 5382insC, or BRCA2 6174delT mutation. None of them reported extreme anxiety and four experienced moderate anxiety that was transitory. Remarkably, five women and six men described their response as neutral. Most carrier women sought medical advice and four underwent risk-reducing procedures after confirmatory mutation testing. Male carriers realized that their test results implied genetic risk for female relatives, and several of them felt considerably burdened by this fact. Sharing mutation information with family members led to screening of at least 30 relatives and identification of 13 additional carriers. Non-carriers did not report inappropriate actions, such as foregoing cancer screening. All but one of the 32 mutation-positive participants

  15. Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families

    PubMed Central

    2013-01-01

    Introduction Population-based studies of breast cancer have estimated that some PALB2 mutations confer a breast cancer risk (penetrance) comparable to the average pathogenic mutation in BRCA2. As this risk is of clinical relevance, we sought to identify mono-allelic PALB2 mutations and determine their frequencies in multiple-case breast cancer families attending Familial Cancer Clinics in Australia and New Zealand. Methods The youngest affected woman, not known to carry a mutation in BRCA1 or BRCA2, from 747 multiple-case breast cancer families participating in kConFab were selected for PALB2 mutation screening. The coding and flanking intronic regions of PALB2 in DNA extracted from blood were screened using high-resolution melt curve analysis with Sanger sequencing confirmation. Where possible, relatives of women found to carry PALB2 mutations were genotyped for the family-specific mutation, mutant transcripts were characterised and breast tumours arising in mutation carriers were recalled and reviewed. Missense mutations were assessed for potential to disrupt protein function via SIFT, Align GVGD and Polyphen-2. Results The mutation screen identified two nonsense mutations (PALB2 c.3113G>A in eight women and PALB2 c.196C>T in one woman), two frameshift mutations (PALB2 c.1947_1948insA and PALB2 c.2982_2983insT each in one woman), 10 missense variants, eight synonymous variants and four variants in intronic regions. Of the four PALB2 mutations identified that were predicted to produce truncated protein products, only PALB2 c.1947_1948insA had not previously been reported. PALB2 c.3113G>A and PALB2 c.196C>T were previously identified in the Australian population whereas PALB2 c.2982_2983insT was previously reported in the UK population. Transcripts derived from three of these mutant PALB2 alleles were vulnerable to nonsense-mediated decay. One missense mutation (PALB2 c.2993G>A) was predicted to disrupt protein function via the three in silico assessment methods

  16. Prevalence and Type of BRCA Mutations in Hispanics Undergoing Genetic Cancer Risk Assessment in the Southwestern United States: A Report From the Clinical Cancer Genetics Community Research Network

    PubMed Central

    Weitzel, Jeffrey N.; Clague, Jessica; Martir-Negron, Arelis; Ogaz, Raquel; Herzog, Josef; Ricker, Charité; Jungbluth, Chelsy; Cina, Cheryl; Duncan, Paul; Unzeitig, Gary; Saldivar, J. Salvador; Beattie, Mary; Feldman, Nancy; Sand, Sharon; Port, Danielle; Barragan, Deborah I.; John, Esther M.; Neuhausen, Susan L.; Larson, Garrett P.

    2013-01-01

    Purpose To determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA). Patients and Methods Hispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board–approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement. Results Deleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States. Conclusion BRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA. PMID:23233716

  17. Response of BRCA1-mutated gallbladder cancer to olaparib: A case report

    PubMed Central

    Xie, Yuan; Jiang, Yan; Yang, Xiao-Bo; Wang, An-Qiang; Zheng, Yong-Chang; Wan, Xue-Shuai; Sang, Xin-Ting; Wang, Kai; Zhang, Da-Dong; Xu, Jia-Jia; Li, Fu-Gen; Zhao, Hai-Tao

    2016-01-01

    Gallbladder cancer (GBC), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. The late diagnosis and abysmal prognosis present challenges to treatment. The overall 5-year survival rate for metastatic GBC patients is extremely low. BRCA1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inh