The Contribution of Germline BRCA1 and BRCA2 Mutations to Familial Ovarian Cancer: No Evidence for Other Ovarian Cancer–Susceptibility Genes

Department of Oncology, Cancer Research Campaign, Strangeways Research Laboratory, Cambridge, United Kingdom.
The American Journal of Human Genetics (Impact Factor: 10.93). 11/1999; 65(4):1021-9. DOI: 10.1086/302583
Source: PubMed


To establish the contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer, we have analyzed both genes in DNA samples obtained from an affected individual in each of 112 families containing at least two cases of epithelial ovarian cancer. Germline mutations were found in 43% of the families; BRCA1 mutations were approximately four times more common than BRCA2 mutations. The extent of family history of ovarian and breast cancers was strongly predictive of BRCA1-mutation status. Segregation analysis suggests that a combination of chance clustering of sporadic cases and insensitivity of mutation detection may account for the remaining families; however, the contribution of other genes cannot be excluded. We discuss the implications for genetic testing and clinical management of familial ovarian cancer arising from the data presented in these studies.

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Available from: Paul Russell, Aug 25, 2015
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    • "The rate of mutations found in families with multiple cases of breast and ovarian cancer varies from 9% to 46%, depending on selection criteria and ethnicity [35– 41]. Among families with at least two cases of epithelial OC, 43% were found to harbor BRCA germline mutations (36% BRCA1 and 7% BRCA2 mutations) [42]. "
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    ABSTRACT: Ovarian cancer (OC) mostly arises sporadically, but a fraction of cases are associated with mutations in BRCA1 and BRCA2 genes. The presence of a BRCA mutation in OC patients has been suggested as a prognostic and predictive factor. In addition, the identification of asymptomatic carriers of such mutations offers an unprecedented opportunity for OC prevention. This review is aimed at exploring the current knowledge on epidemiological and molecular aspects of BRCA-associated OC predisposition, on pathology and clinical behavior of OC occurring in BRCA mutation carriers, and on the available options for managing asymptomatic carriers.
    BioMed Research International 07/2014; 2014:787143. DOI:10.1155/2014/787143 · 3.17 Impact Factor
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    • "For many years, hereditary ovarian cancer was thought to be mainly, if not entirely, attributable to mutations in the BRCA1/ BRCA2 breast cancer susceptibility genes (Gayther et al, 1999). While mutations in additional genes such as PALB2, CHEK2, ATM, and BRIP1 were also found to predispose to breast cancer (Shuen and Foulkes, 2011), until recently, no other genes were found to be mutated in hereditary ovarian cancer. "
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    ABSTRACT: Recent data show that mutations in RAD51D have an aetiological role in ovarian carcinoma, yet mutations do not appear to be associated with an increased risk for breast cancer. We studied ovarian and breast cancer families having at least one woman affected by ovarian carcinoma, to assess the importance of RAD51D mutations in such families. The coding region of the RAD51D gene was analysed in 175 BRCA1/2-negative families with family histories of both ovarian and breast cancer ascertained from two Canadian and two Belgian institutions. We identified one previously reported deleterious mutation, p.Arg186(*) (c.556C>T), and two novel variants; missense substitution p.Cys119Arg and an intronic variant c.83-26A>G. p.Arg186(*) segregated with the disease in the family and two ovarian carcinomas available for analysis showed loss of the wild-type allele, but the novel variants are likely neutral. RAD51D should be included in genetic screening of ovarian cancer families that do not have BRCA1/BRCA2 mutations. We show that mutations are more likely to be found in families with two or more ovarian cancers, or in probands with first-degree relatives with ovarian cancer, and we feel testing should be preferentially offered to affected women from such families.
    British Journal of Cancer 03/2012; 106(8):1460-3. DOI:10.1038/bjc.2012.87 · 4.84 Impact Factor
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    • "Seven pathogenic mutations (including one novel pathogenic mutation) have been identified (5 BRCA1 and 2 BRCA2) in 8/70 (11.4%) families. Our results indicate, as has been documented by others, that family history is the major determinant of the risk of breast cancer [14] [15] [16] [17] [18]. As shown in Table 2, in all families where a pathogenic mutation was identified, there was a family history of breast cancer. "
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    ABSTRACT: Breast cancer is the leading cause of cancer death in women in Algeria. The contribution of BRCA1 and BRCA2 mutations to hereditary breast/ovarian cancer in Algerian population is largely unknown. Here, we describe analysis of BRCA1 and BRCA2 genes in 86 individuals from 70 families from an Algerian cohort with a personal and family history suggestive of genetic predisposition to breast cancer. The approach used is based on BRCA1 and BRCA2 mutations screening by High-Resolution Melting (HRM) curve analysis followed by direct sequencing. All samples for which no pathogenic mutation was found were analyzed by MLPA for large deletions or duplications. Three distinct pathogenic mutations c.83_84delTG, c.181T>G, c.798_799delTT and two large rearrangements involving deletion of exon 2 and exon 8 respectively, were detected in BRCA1 gene. Moreover 17 unclassified variants and polymorphisms were detected in BRCA1 gene (6 described for the first time). Two pathogenic mutations, c.1310_1313delAAGA and c.5722_5723delCT and 40 unclassified variants and polymorphisms (14 never described before) were identified in BRCA2 gene. For the first time, we used HRM and MLPA to identify BRCA1 and BRCA2 mutations in Algerian patients with a personal and family history suggestive of genetic predisposition to breast cancer. The implications of these new findings in regard to genetic testing and counseling are substantial for the Algerian population.
    Disease markers 08/2010; 28(6):377-84. DOI:10.3233/DMA-2010-0718 · 1.56 Impact Factor
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