Rates of Jewish Ancestral Mutations in BRCAI and BRCA2 in Borderline Ovarian Tumors

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Abstract
Background: Germline mutations in the BRCA1 and BRCA2 genes are known to be associated with an increased risk of breast and epithelial ovarian cancers. Two specific mutations, 185delAG-BRCAl and 6174de1TBRCA2, have been detected in a substantial proportion (20%–60%) of unselected Ashkenazi Jewish patients - i.e., Jewish patients of Eastern/Northern European descent-with invasive ovarian cancer and in a measurable proportion (2%) of the general Ashkenazi Jewish population. However, uncertainty exists concerning the heritable basis of borderline ovarian tumors and whether these tumors represent an early form of ultimately invasive disease. To gain insight into these issues, we determined the rates of 185delAG-BRCA1 and 6174de1TBRCA2 mutations in patients with borderline ovarian tumors. Methods: Analysis of 185delAG-BRCA1 and 6174de1T-BRCA2 germline mutations was performed by use of a heteroduplex formation assay in samples from 46 consecutive patients with borderline ovarian tumors and 59 consecutive patients with invasive epithelial ovarian cancers. Forty-eight samples were also analyzed by restriction enzyme analysis for the presence of the 5382insCBRCA1 mutation, a mutation detected in 2.2% of Ashkenazi Jewish patients with breast, but not ovarian, cancer. Results: One (2.2%) of the 46 patient with borderline tumors was identified as a carrier of the 185delAG-BRCAl mutation, and no patients were found to carry the 6174de1T-BRCA2 muta tion. Nineteen (32%) of the 59 patients with invasive ovarian cancer were found to carry one of these two mutations; 17 carried 185delAG-BRCAl and two carried 6174de1T-BRCA2 (χ2 test with continuity correction, P = .00028). None of the patients analyzed for 5382insC-BRCAl were found to carry the mutation. In one high-risk family that included 185delAG-BRCAl carriers, a single patient with stage IIIc borderline ovarian tumor did not carry the mutation. Conclusions: Invasive epithelial and borderline ovarian tumors appear to differ in their genetic predisposition and in the molecular mechanisms underlying their genesis. [J Nall Cancer Inst 1998;90:995–1000]