Telomerase Independent Telomere Maintenance in Ovarian Cancer: A Molecular Genetic Analysis

摘要

The goal of this project is to elucidate some of the genetic and biological determinants of ovarian cancer, focusing on an in vitro model for ovarian cancer that we have developed. We found that immortalization and transformation of human ovarian surface epithelial (HOSE) cells can differ in the pathway used for telomere length maintenance, a phenomenon that we have also observed in the clinical disease. We have found that the majority of our HOSE cell cultures use the Alternative Lengthing of Telomeres (ALT) pathway for telomere maintenance, thereby providing an in vitro model to characterize the underlying basis of the ALT pathway in ovarian cancer. We completed Task 1 having characterized telomere dynamics in 50 ovarian tumors, created a number of cDNA custom microarrays and used these resources to assess expression differences in clinical samples. As proposed in Task 2, we successfully reintroduced telomerase into several HOSE cell lines and have identified two telomeric factors, TRF2 and Tankyrase2, whose expression is altered following forced expression of telomerase in ALT positive cells. Finally, as intended in Task 3 we have demonstrated that the tumor suppressor p53 negatively regulates ALT, the first identification of regulatory requirements for ALT.