The molecular pathogenesis of hereditary ovarian carcinoma: alterations in the tubal epithelium of women with BRCA1 and BRCA2 mutations.

Abstract

BRCA1 or BRCA2 (BRCA1/2)-mutated ovarian carcinomas may originate in the fallopian tube. The authors of this report investigated alterations in BRCA1/2 tubal epithelium to define the molecular pathogenesis of these carcinomas. Tubal epithelium was evaluated from 31 BRCA1/2 mutation carriers with gynecologic carcinomas (BRCA CA), 89 mutation carriers who underwent risk-reducing salpingo-oophorectomy (RRSO), and 87 controls. Ki-67 expression and p53 foci (≥10 of 12 consecutive staining cells) were scored by 2 investigators who were blinded to patient designations. Expression levels of p27 and p21 were evaluated within p53 foci. Loss of heterozygosity at the BRCA1/2 mutation site was evaluated in microdissected p53 foci and tubal neoplasms. Background tubal proliferation as measured by Ki-67 staining was increased in the BRCA1 RRSO group (P = .005) compared with the control group. Women who had BRCA1/2 mutations had more p53 foci identified per tubal segment than women in the control group (P = .02). Levels of p27 were decreased in 12 of 28 p53 foci from women with BRCA1 mutations and in 0 of 16 p53 foci from controls (P = .002). There was no loss of the wild type BRCA1/2 allele in 5 tested p53 foci. Tubal neoplasia lost the wild type allele in 6 of 6 foci (P = .002). The current results suggested a model of tubal carcinogenesis in women with BRCA1/2 mutations. Increased proliferation occurred globally in at-risk tubal epithelium. A mutation in the tumor protein p53 gene TP53 with clonal proliferation and loss of p27 occurred before neoplastic proliferation. Loss of the wild type BRCA1/2 allele occurred with neoplastic proliferation and before invasion.