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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    • "In addition, many studies suggest that genetic factors play an important role in the etiology of ovarian cancer. Germline mutations in the high penetrance genes BRCA1 and BRCA2 have been reported to be associated with ovarian cancer (Gayther et al., 1999). Folate is indispensably required for DNA synthesis, and the methylation of DNA and histones. "
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    ABSTRACT: Numerous studies have evaluated the association between the MTHFR A1298C polymorphism and ovarian cancer risk. However, the specific association is still controversial. Therefore, we performed the present meta-analysis. A systematic literature search of PubMed and Embase databases was undertaken in August 2014, and the reference lists of articles were retrieved. ORs with their 95%CI were calculated to evaluate the strength of the association. Meta-analysis was performed using the STATA version 12.0 software package and publication bias was investigated by Begg's funnel plot. Five case-control studies from three publications (with 7026 subjects) on the relationship between the MTHFR A1298C polymorphism and ovarian cancer were analyzed by meta-analysis. Overall, no significant variation in ovarian cancer risk was detected in any of the genetic models (AA vs CC: OR = 0.93, 95%CI = 0.78-1.10; AA vs AC: OR = 1.02, 95%CI = 0.92-1.13; dominant model: OR = 1.00, 95%CI = 0.91-1.10; recessive model: OR = 0.92, 95%CI = 0.78-1.08). In conclusion, this meta-analysis suggests that the A1298C polymorphism in the MTHFR gene may be not associated with susceptibility to ovarian cancer.
    Preview · Article · Sep 2015 · Genetics and molecular research: GMR
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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.
    Full-text · Article · Jul 2014 · BioMed Research International
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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.
    Full-text · Article · Mar 2012 · British Journal of Cancer
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