Telomeric instability and reduced proliferative potential in ovarian surface epithelial cells from women with a family history of ovarian cancer

Objective. Increased telomeric instability in normal ovarian surface epithelium may contribute to ovarian carcinogenesis in women from families with a high frequency of breast/ovarian cancer. To test this hypothesis, we compared proliferative potential, mean telomeric length, and telomerase activity in SV-40 large T-antigen transfected cell lines derived from normal ovarian surface epithelium of women with and without a familial history of breast/ovarian cancer. Methods. Telomeric instability was examined in SV-40 large T-antigen transfected cell lines of normal ovarian surface epithelium from patients with (FHIOSE, N = 5) and without (NFHIOSE, N = 11) a history of familial breast/ovarian cancer, The duration and total attainable number of population doublings, mean telomeric length, rate of telomeric loss, and telomerase activity were determined by cell counts, Southern blot analysis, and PCR ELISA. Results. FHIOSE cells attained fewer population doublings than NFHIOSE cells and doubled at approximately half the rate of NFHIOSE cells, indicating a reduced proliferative capacity in FHIOSE cells. While telomerase activity was not detected in FHIOSE or NFHIOSE cell lines, mean telomeric lengths in FHIOSE were generally 1 kb shorter than in NFHIOSE cells and the rate of telomeric loss as a function of population doublings was up to threefold greater in FHIOSE cells, Conclusions. Increased telomeric instability and reduced growth potential suggest greater proximity to replicative senescence in ovarian surface epithelium from women with a familial history of breast/ ovarian cancer. Consequently, an accumulation of genetic aberrations due to accelerated cellular aging may contribute to the enhanced susceptibility for malignant transformation and earlier onset in heritable ovarian cancer. (C) 1999 Academic Press.