BRCA1 germline mutations and polymorphisms in a clinic-based series of ovarian cancer cases: A gynecologic oncology group study

Objective. The aims of this study were to determine the frequency of BRCA1 gene alterations in an unselected, clinic-based series of ovarian cancer cases; to evaluate the usefulness of family history in predicting the likelihood of a disease-causing mutation; and to document the occurrence of polymorphic variants in BRCA1 and to determine their distribution among families accordingly to history of breast and/or ovarian cancer. Method. Two hundred fifty-eight women with primary epithelial ovarian cancer, entered onto a nonclinical protocol of the Gynecologic Oncology Group, were analyzed for BRCA1 germline alterations by single-strand conformation polymorphism analysis. Results. Protein-truncating mutations in BRCA1 were identified in 12 patients (4.6%). The median age of cancer diagnosis in BRCA1 mutation carriers was 47 years compared to 57 years in patients without mutations (P = 0.02). All but 1 of the patients with BRCA1 mutations reported a family history of breast and/or ovarian cancer and 8 had a first-degree relative with cancer. Twelve mutations of unknown significance were also identified. An association was also noted between the presence of common polymorphisms in BRCA1 and family history of cancer. Polymorphisms were present at higher frequency among women without a family history of cancer compared to women with positive family histories, suggesting they are associated with reduced risk. Conclusion. In a clinic-based series of ovarian cancer patients, germline BRCA1 mutations were detected in 12 of 258 (4.6%) patients. A strong correlation was noted between the presence of mutations and family history of breast and/or ovarian cancer, indicating that these women are most likely to benefit from genetic susceptibility testing.