BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer

Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
Cancer (Impact Factor: 4.89). 05/2009; 115(10):2222-33. DOI: 10.1002/cncr.24200
Source: PubMed


In women at increased risk for breast and ovarian cancer, the identification of a mutation in breast cancer gene 1 (BRCA1) and BRCA2 has important implications for screening and prevention counseling. Uncertainty regarding the role of BRCA1 and BRCA2 testing in high-risk women from diverse ancestral backgrounds exists because of variability in prevalence estimates of deleterious (disease-associated) mutations in non-white populations. In this study, the authors examined the prevalence of BRCA1 and BRCA2 mutations in an ethnically diverse group of women who were referred for genetic testing.
In this cross-sectional analysis, the prevalence of BRCA1 and BRCA2 mutations was assessed in a group of non-Ashkenazi Jewish women who underwent genetic testing.
From 1996 to 2006, 46,276 women who met study criteria underwent DNA full-sequence analysis of the BRCA1 and BRCA2 genes. Deleterious mutations were identified in 12.5% of women, and recurrent deleterious mutations (prevalence >2%) were identified in all ancestral groups. Women of non-European descent were younger (mean age, 45.9 years; standard deviation [SD], 11.6 years) than European women (mean age, 50 years; SD, 11.9 years; P < .001). Women of African (15.6%; odds ratio [OR], 1.3 [95% confidence interval (95% CI), 1.1-1.5]) and Latin American (14.8%; OR, 1.2 [95% CI, 1.1-1.4]) ancestries had a significantly higher prevalence of deleterious BRCA1 and BRCA2 mutations compared with women of Western European ancestry (12.1%), primarily because of an increased prevalence of BRCA1 mutations in those 2 groups. Non-European ethnicity was associated strongly with having a variant of uncertain significance; however, reclassification decreased variant reporting (from 12.8%-->5.9%), and women of African ancestry experienced the largest decline (58%).
Mutation prevalence was found to be high among women who were referred for clinical BRCA1 and BRCA2 testing, and the risk was similar across diverse ethnicities. BRCA1 and BRCA2 testing is integral to cancer risk assessment in all high-risk women.

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Available from: Dmitry Pruss, Oct 28, 2014
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    • "Since the identification of the BRCA1/2 genes, a number of studies to evaluate epidemiologic characteristics of BRCA1/2 mutations among diverse ethnicities have been conducted [12-15]. Earlier studies of BRCA1/2 mutations were largely based on Caucasian populations; however, a number of recent studies have focused on Asian patients in order to define the distributions of these genetic mutations in the Asian population [16-29]. "
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    ABSTRACT: Breast cancer is the most prevalent cancer in Asian females, and the incidence of breast cancer has been increasing in Asia. Because Asian patients develop breast cancer at a younger age than their Caucasian counterparts, the contributions of BRCA1 and BRCA2 (BRCA1/2) mutations in Asians are expected to be different than in Caucasians. The prevalence of BRCA1/2 mutations in the Asian population varies among countries and studies. Most Asian studies have reported more frequent mutations in BRCA2 than in BRCA1, with the exception of studies from India and Pakistan. In addition, the contribution of large genomic rearrangements of BRCA1/2 genes is relatively small in Asian populations in comparison to other ethnic populations. Various statistical models for the prediction of BRCA1/2 mutations have underestimated the risk of having these genetic mutations in Asians, especially in predicting BRCA2 gene mutation. Until recently, BRCA1/2 mutation analyses in Asia were mostly conducted by independent single institutions with different patient selection criteria and using various genotyping methods. However, a couple of Asian groups have initiated nationwide studies collecting BRCA1/2 mutational data. These national collaborative studies will help a comprehensive understanding of the prevalence of BRCA1/2 mutations in the Asian population.
    Journal of Breast Cancer 12/2013; 16(4):357-365. DOI:10.4048/jbc.2013.16.4.357 · 1.58 Impact Factor
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    • "found to carry a BRCA1 variant of uncertain significance (VUS). These variants were classified as uncertain because they occurred in families wherein segregation analysis had not been done or in whom the segregation analysis was not informative and thus the VUS had unknown effects on breast and ovarian cancer risk [Hall et al., 2009; Spearman et al., 2008; Sweet et al., 2009]. As whole genome and exome sequencing becomes a more prevalent practice, more VUSs in BRCA1 will be uncovered, and increasingly women will face the quandary of an uninformative genetic test. "
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    ABSTRACT: Missense substitutions of uncertain clinical significance in the BRCA1 gene are a vexing problem in genetic counseling for women who have a family history of breast cancer. In this study, we evaluated the functions of 29 missense substitutions of BRCA1 in two DNA repair pathways. Repair of double strand breaks by homology directed recombination (HDR) had been previously analyzed for 16 of these BRCA1 variants, and 13 more variants were analyzed in this study. All 29 variants were also analyzed for function in double strand break repair by the single strand annealing (SSA) pathway. We found that among the pathogenic mutations in BRCA1, all were defective for DNA repair by either pathway. The HDR assay was accurate since all pathogenic mutants were defective for HDR, and all non-pathogenic variants were fully functional for HDR. Repair by SSA accurately identified pathogenic mutants, but several non-pathogenic variants were scored as defective or partially defective. These results indicated that specific amino acid residues of the BRCA1 protein have different effects in the two related DNA repair pathways, and these results validate the HDR assay as highly correlative with BRCA1-associated breast cancer.
    Human Mutation 03/2013; 34(3). DOI:10.1002/humu.22251 · 5.14 Impact Factor
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    • "The low prevalence of mutations found in our population in comparison to other ones [5,18-20], can be explained either by the genetic testing criteria, or by the possibility that some mutations were missed since we could not look for deletions or duplications of entire exons. Consanguinity might be also an equivocal risk-modifying factor [21,22]. "
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    ABSTRACT: Breast cancer is the most prevalent malignancy in women in Western countries, currently accounting for one third of all female cancers. Familial aggregation is thought to account for 5–10 % of all BC cases, and germline mutations in BRCA1 and BRCA2 account for less of the half of these inherited cases. In Lebanon, breast cancer represents the principal death-causing malignancy among women, with 50 % of the cases diagnosed before the age of 50 years. In order to study BRCA1/2 mutation spectra in the Lebanese population, 72 unrelated patients with a reported family history of breast and/or ovarian cancers or with an early onset breast cancer were tested. Fluorescent direct sequencing of the entire coding region and intronic sequences flanking each exon was performed. A total of 38 BRCA1 and 40 BRCA2 sequence variants were found. Seventeen of them were novel. Seven confirmed deleterious mutations were identified in 9 subjects providing a frequency of mutations of 12.5 %. Fifteen variants were considered of unknown clinical significance according to BIC and UMD-BRCA1/BRCA2 databases. In conclusion, this study represents the first evaluation of the deleterious and unclassified genetic variants in the BRCA1/2 genes found in a Lebanese population with a relatively high risk of breast cancer.
    Hereditary Cancer in Clinical Practice 06/2012; 10(1):7. DOI:10.1186/1897-4287-10-7 · 1.47 Impact Factor
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