Abstract
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.
Highlights
Ovarian cancer is one of the highest mortality rated malignancies, an aspect mainly attributed to the advanced stage at diagnosis
Familial cases were further screened for mutations in all BRCA1 exons where a mutation was previously identified in the Greek population, increasing mutation prevalence in this group to 40.6% (43/106)
In this study we have established the prevalence of BRCA1 mutations in a group of 698 Greek ovarian cancer patients, 106 of which were familial cases and 592 apparently sporadic
Summary
Ovarian cancer is one of the highest mortality rated malignancies, an aspect mainly attributed to the advanced stage at diagnosis. Carriers of inherited mutations in BRCA1 and BRCA2 genes face a lifetime risk of ovarian cancer of 35–60% (average age of diagnosis 50 years) and 12–25% (average age of diagnosis 60 years) respectively, and an elevated risk of fallopian tube and peritoneal carcinomas [1,2,3]. The BRCA1/2 mutation status of an ovarian cancer patient can be an important aspect in regards to the decision of chemotherapy; BRCA1/2 carriers show increased sensitivity to platinum-based therapy [6,7], as well as to poly-ADP-ribose polymerase inhibitors [8]. The cumulative risk of ovarian cancer in MMR mutation carriers is estimated to be 10%, while histologically these tumours are of the endometrioid subtype in most cases [9]
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