PARK2, a Large Common Fragile Site Gene, is Part of a Stress Response Network in Normal Cells that is Disrupted During the Development of Ovarian Cancer; Final addendum rept. 15 Dec 2006-14 Dec 2007

摘要

PARK2 (Parkin) is a common fragile site (CFS) gene. We examined Parkin in primary ovarian tumors and found that this gene was frequently inactivated. We also found that re-introduction of Parkin is associated with greater sensitivity to apoptotic induction in ovarian cancer cell lines. We also discovered an entire family of very large common fragile site genes. We measured the expression of Parkin and 13 other CFS genes in panels of different cancers. This revealed non-random inactivation of these genes and greater inactivation in cancers that have a poorer clinical prognosis. We then utilized whole genome tiling arrays to characterize all transcripts (not just coding transcripts) and their response to stress. These studies revealed non-coding transcripts within Parkin and other large CFS genes. We discovered a new class of large non-coding transcripts. A sub-set of these were highly evolutionarily conserved; when we examined these transcripts in ovarian and other cancers, we found alterations in their expression. We also found that some of these non- coding transcripts were mutational targets in ovarian and other cancers. Thus, this work has discovered a new group of targets that are altered during the development of ovarian cancer.