[752] Characterization of Complex Chromosomal Aberrations in Primary Prostate Cancer Genomes.

Michael F Berger, Michael S Lawrence, Francesca Demichelis, Gad Getz, Mark A Rubin, Levi A Garraway, For the Broad Institute and Weill Cornell Medical College Prostate Genome Consortium. The Broad Institute, Cambridge; Weill Cornell Medical College, New York; Harvard Medical School, Boston; Dana-Farber Cancer Institute, Boston

Background: Prostate cancer remains the second most common cause of male cancer deaths in the United States. Although androgen withdrawal and/or antagonism-based treatment of advanced disease yields transient efficacy, most patients with relapsed or metastatic prostate cancer eventually die of their disease. These aspects underscore the critical need to articulate both genetic underpinnings and novel therapeutic targets in prostate cancer. Here we present the complete sequence of seven “high-risk” primary prostate cancers and their matched normal counterparts.
Design: Seven prostate cancers were selected from “high-risk”, clinically localized tumors that were at least 80% enriched for tumor cells. Cancer and germline genomes were sequenced at 30 fold coverage.
Results: The average point mutation rate in these tumors was 1.0 per Megabase. Each prostate tumor also harbored dozens of chromosomal rearrangements, and several tumors contained complex patterns of balanced chromosomal breakpoints that occurred within or adjacent to several predicted cancer genes (See Table for details).

Rearrangement breakpoints were significantly associated with open chromatin, androgen receptor and ERG DNA binding sites in the setting of the TMPRSS2-ERG gene fusion, but inversely correlated with these regions in tumors lacking ETS gene fusions. Three ETS-negative tumors contained rearrangements that disrupted CADM2, indicative of a novel prostate cancer tumor suppressor mechanism. Furthermore, four of seven prostate tumors harbored chromosomal rearrangements disrupting either PTEN (unbalanced events), a prostate tumor suppressor; or a PTEN interacting protein not previously implicated in prostate tumorigenesis.
Conclusions: Together, these findings implicate chromatin and transcriptional regulation in the genesis of prostate cancer genomic aberrations and suggest that complex rearrangements engage multiple tumorigenic mechanisms in this malignancy.
Category: Genitourinary (including renal tumors)

Monday, February 28, 2011 1:00 PM

Poster Session II # 107, Monday Afternoon


Close Window