Expression of differentiation and proliferation related proteins in epithelium of prophylactically removed ovaries from women with a hereditary female adnexal cancer predisposition.

AIMS: To investigate the occurrence of preinvasive neoplastic lesions in ovarian surface epithelium and ovarian inclusion cyst epithelium of women with a hereditary predisposition to the development of female adnexal (ovarian and fallopian tube) carcinoma and to assess the expression of differentiation and proliferation related proteins within putative sites of origin of serous ovarian carcinoma, the ovarian surface epithelium and ovarian inclusion cyst epithelium. METHODS: Twenty-one ovaries, prophylactically removed from 11 women predisposed to the development of female adnexal cancer (cases) were compared with 22 ovaries from 11 women without such predisposition (controls). Archival histological specimens were screened for hyperplastic and dysplastic epithelial lesions. In both the ovarian surface and inclusion cyst epithelia, the percentage of cells was determined that stained positively for Ki67, p21, p27, p53, cyclin A, cyclin D1, bcl-2 and the presence of HER-2/neu, oestrogen (ER-alpha) and progesterone receptors (PR). RESULTS: No preinvasive neoplastic lesions were detected. However, hyperplastic areas were found in three cases and in four controls (NS). ER-alpha (P = 0.013), PR (P < 0.001), bcl-2 (P = 0.008), p21 (P = 0.046) and p27 (P = 0.008) were expressed in a significantly higher percentage of cells in inclusion cyst epithelium than in ovarian surface epithelium (both groups). The latter showed higher bcl-2 expression in cases (P = 0.05) compared with controls. The inclusion cyst epithelium of cases showed higher expression of bcl-2 (P = 0.006) and PR (P = 0.039) compared with controls. Proliferation was low in both cases and controls as reflected by low Ki67 expression. Over-expression of p53, cyclin D1 and HER-2/neu was not detected. CONCLUSIONS: Premalignant changes are not a common feature of ovaries removed prophylactically from women predisposed to the development of female adnexal carcinoma. Increased expression of p21, p27, and ER-alpha is seen in inclusion cyst compared with ovarian surface epithelium of women with and without an inherited risk of adnexal carcinoma. This is most probably caused by the different intraovarian hormonal milieu of inclusion cyst epithelium. However, the increased expression of bcl-2 and PR in the inclusion cyst epithelium of patients with a hereditary predisposition may reflect early disruption of hormonal balance and growth control.

Molecular evidence for putative tumour suppressor genes on chromosome 13q specific to BRCA1 related ovarian and fallopian tube cancer.

BACKGROUND/AIMS: Loss of heterozygosity (LOH) on chromosome 13q has been reported to occur frequently in human ovarian cancer, and indications have been found that chromosome 13 may also play a specific role in the inherited form of ovarian cancer. The aim of this study was to define regions on chromosome 13 that may harbour additional tumour suppressor genes involved in the tumorigenesis of BRCA1 related ovarian and fallopian tube cancer. MATERIALS/METHODS: DNA extracted from paraffin wax blocks of 36 BRCA1 associated ovarian and fallopian tube carcinomas was analysed by LOH polymerase chain reaction using seven highly polymorphic microsatellite markers spanning chromosome 13q. RESULTS: High LOH frequencies were found on loci 13q11, 13q14, 13q21, 13q22-31, 13q32, and 13q32-4, suggesting the presence of putative tumour suppressor genes on the long arm of chromosome 13 that may play a role in the pathogenesis of BRCA1 related ovarian and fallopian tube cancer. LOH patterns appeared to be independent of the type of BRCA1 mutation, stage, and grade. Although in some cases there were indications for loss of larger parts of chromosome 13, in most cases losses were fairly randomly distributed over chromosome 13 with retained parts in between lost parts. Microsatellite instability was found in six cases. CONCLUSION: Several loci on chromosome 13q show high frequencies of LOH in BRCA1 related ovarian and fallopian tube cancer, and may therefore harbour putative tumour suppressor genes involved in the carcinogenesis of this particular type of hereditary cancer.