Genetic analysis of aberrant histological structures in prophylactic oophorectomy specimens from women with germline BRCA1 and BRCA2 mutations

Abstract

Ovarian cancer is the fifth most frequent cause of overall cancer related death for women in the Western World (Iwabuchi et al, 1995; Shelling et al, 1995). It has been estimated that inherited mutations of the breast and ovarian cancer susceptibility gene BRCA1 will be detected in 5% of common epithelial malignant ovarian tumours. The lifetime risk of ovarian or breast cancer development for women with BRCA1 mutations approaches 100% (Ford et al, 1994). As a result, some women with mutations elect to undergo prophylactic oophorectomy after completion of childbearing, in order to reduce the likelihood of tumour development. This study is based on the findings of Salazar et al (1996), who reported a significantly higher incidence of atypical features in the ovaries of BRCA1 mutation carriers when compared to a control population, raising the possibility of a histological pre-malignant phenotype. We examined prophylactic oophorectomy specimens from six women, five with BRCA1 mutations, and the other a BRCA2 mutant. DNA was extracted from microdissected areas of atypia within sections of paraffin-embedded ovarian tissue. Matched leucocyte DNA was obtained for comparison. Microsatellite PCR was used to examine for loss of heterozygosity (LOH) at candidate loci on all chromosome arms. Amongst BRCA1 carriers, we were able to identify LOH in both inclusion cyst material and in areas of microscopic malignancy incidentally discovered. Material from the BRCA2 mutant showed no LOH. The LOH detected was in keeping with that previously reported for ovarian tumours. The data we have obtained supports the concept of a histological pre-malignant phenotype in ovaries of women with BRCA1 mutations.

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