Exome Sequencing and Integrative Mutational Profiling of Lethal Castrate Resistant Prostate Cancer
Scott A Tomlins, Catherine S Grasso, Dan R Robinson, Yi-Mi Wu, Saravana Dhanasekaran, Michael J Quist, Xuhong Cao, Xiaojun Jing, John C Brenner, Daniel R Rhodes, Kenneth J Pienta, Arul M Chinnaiyan. Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI; Compendia Biosciences and University of Michigan Medical School, Ann Arbor, MI
Background: Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and AR amplification, that drive prostate cancer development and progression to lethal metastatic castrate resistant prostate cancer (CRPC). As less is known about the role of mutations, we sequenced the exomes of 21 lethal CRPCs (including three different foci from the same patient) and 3 localized prostate cancers.
Design: Exome libraries were generated from matched tumor/normal DNA pairs and sequenced with the Illumina GAII Genome Analyzer or the Illumina HiSeq in paired end mode. Results were integrated with a compendium of related genomic data, including a novel large matched gene expression/aCGH data set.
Results: Exome sequencing demonstrated low overall mutation rates even in heavily treated CRPC (2.23/Mb) and confirmed the monoclonal origin of lethal CRPC. No genes were highly mutated (>50% of cases), however we identified three known (AR, TP53, and ZFHX3) and two novel genes as significantly mutated in prostate cancer. Through integration with a compendium of related genomic data, we confirm deregulation of genes known to play driving roles in prostate cancer and nominate genes recurrently disrupted, including GRM1, STAG2, the ETS family member ETS2 and genes at 5q21 (in ETS fusion-/PTEN deletion- cancers). Finally, we identified novel recurrent mutations in an AR collaborating factor which disrupt androgen signaling and increase proliferation.
Conclusions: Through our integrative analysis, we provide a global description of the mutational landscape of CRPC and prioritize candidates for future study. Updated results on over 40 CRPC will be presented.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 2, Monday Morning