Title: Discovery of Novel Gene Elements Associated with Prostate Cancer Progression Discovery of Novel Gene Elements Associated with Prostate Cancer Progression Arul Chinnaiyan Approved for Public Release; Distribution Unlimited

High-throughput sequencing of polyA+ RNA (RNA-Seq) in human cancer shows remarkable potential to identify both novel markers of disease and uncharacterized aspects of tumor biology, particularly non-coding RNA (ncRNA) species. We employed RNA-Seq on a cohort of 102 prostate tissues and cells lines and performed ab initio transcriptome assembly to discover unannotated ncRNAs. We nominated 121 such Prostate Cancer Associated Transcripts (PCATs) with cancer-specific expression patterns. Among these, we characterized PCAT-1 as a novel prostate-specific regulator of cell proliferation and target of the Polycomb Repressive Complex 2 (PRC2). We further found that high PCAT-1 and PRC2 expression stratified patient tissues into molecular subtypes distinguished by expression signatures of PCAT-1-repressed target genes. Taken together, the findings presented herein identify PCAT-1 as a novel transcriptional repressor Please address requests to: Arul M. Chinnaiyan, M.D., Ph.D., Michigan Center for Translational Pathology, University of Michigan Medical School, 1400 E. Medical Center Dr, 5316 Cancer Center, Ann Arbor, Michigan 48109-0602 Phone: (734) 615-4062 Fax: (734) 615-4498 ([email protected]). 8These authors contributed equally Author Contributions M.K.I., J.R.P. and A.M.C. designed the project and directed experimental studies. M.K.I., O.A.B., C.G., and C.A.M. developed computational platforms and performed sequencing data analysis. M.K.I, O.A.B., and H.I. performed statistical analyses. J.R.P., S.M.D., J.C.B., Q.C., N.P., H.D.K., B.L., X.W., and D.R. performed experimental studies. J.S. and J.T.W. coordinated biospecimens. M.K.I., J.R.P. and A.M.C. interpreted data and wrote the manuscript. Data Deposition Data from RNA-Seq experiments are deposited at the NCBI Gene Expression Omnibus as GSE25183. PCAT-1 and PCAT-14 nucleotide sequences are deposited at GenBank as HQ605084 and HQ605085, respectively. Disclosures and Competing Financial Interests The University of Michigan has filed for a patent on the detection of gene fusions in prostate cancer, on which A.M.C. is a co-inventor. The diagnostic field of use for ETS gene fusions has been licensed to GenProbe Inc. The University of Michigan has a sponsored research agreement with GenProbe which is unrelated to this study. GenProbe has had no role in the design or experimentation of this study, nor has it participated in the writing of the manuscript. NIH Public Access