Absence of premalignant histologic, molecular, or cell biologic alterations in prophylactic oophorectomy specimens from BRCA1 heterozygotes

BACKGROUND. The high mortality associated with ovarian carcinoma is largely a reflection of the inability to diagnose the disease at an early stage; t he identification of a histologic lesion or molecular marker associated ear ly stages of transformation would represent an important advance in underst anding the natural history of this cancer. The existence of individuals wit h germline mutations in the ovarian and breast carcinoma susceptibility gen e BRCA1 represents a unique opportunity to search for such premalignant alt erations in ovarian tissues that are at unusually high risk for tumorigenes is. In this study, the authors addressed the hypothesis that pathologically normal ovaries removed from BRCA1 heterozygotes are likely to display prem alignant histologic, molecular, and/or cell biologic alterations that may p rovide insight into early stages of ovarian tumorigenesis. METHODS, Ovarian tissues from 18 BRCA1 heterozygotes and from 20 age-matche d controls were examined in a blinded fashion for histologic evidence of su rface epithelial pseudostratification, epithelial inclusion cysts, deep cor tical invaginations of surface epithelium, increased stromal cell activity, and surface papillomatosis. Immunohistochemical analyses for expression of BRCA1, p53, and ERBB-2 and quantitation of cell proliferation (Ki-67 expre ssion) and apoptosis (TUNEL assay), were also performed on all specimens. RESULTS. Although histologic alterations were observed, there was no differ ence in frequency between cases and controls. Analysis of BRCA1 expression revealed ubiquitous nuclear immunoreactivity in the surface epithelial cell s of all ovaries. Similarly no evidence was found of p53 overexpression in any ovarian tissue or of a difference in ERBB-2 expression between cases an d controls. Finally, no differences were observed in epithelial cell prolif eration or apoptosis. CONCLUSIONS, Clinically, normal ovaries from BRCA1 heterozygotes do not sho w evidence of premalignant alterations in histology, molecular markers, cel l proliferation, or apoptosis, indicating that such changes are likely rare . (C) 2000 American Cancer Society.