There is a clear need to improve risk stratification and identify novel therapeutic targets in aggressive prostate cancer. The goal of this study was to investigate genes with outlier expression with prognostic association in high-risk prostate cancer patients as potential biomarkers and drug targets.
We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13. 4y). Three independent clinical datasets totaling an additional 545 patients were used for validation. Novel prognostic outlier genes were interrogated for impact on oncogenic phenotypes in vitro using siRNA-based knockdown. Association with clinical outcomes and comparison with existing prognostic instruments was assessed with multivariable models using a prognostic outlier score.
Analysis of the discovery cohort identified 20 prognostic outlier genes. Three top prognostic outlier genes were novel prostate cancer genes; NVL, SMC4, or SQLE knockdown reduced migration and/or invasion and outlier expression was significantly associated with poor prognosis. Increased prognostic outlier score was significantly associated with poor prognosis independent of standard clinicopathologic variables. Finally, the prognostic outlier score prognostic association is independent of, and adds to existing genomic and clinical tools for prognostication in prostate cancer (Decipher, the cell cycle progression (CCP) signature, and CAPRA-S).
To our knowledge, this study represents the first unbiased high-throughput investigation of prognostic outlier genes in prostate cancer and demonstrates the potential biomarker and therapeutic importance of this previously unstudied class of cancer genes.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2015 Dec 02 [Epub ahead of print]
Shuang G Zhao, Joseph R Evans, Vishal Kothari, Grace Sun, Ashley Larm, Victor Mondine, Edward M Schaeffer, Ashley E Ross, Eric A Klein, Robert B Den, Adam P Dicker, R Jeffrey Karnes, Nicholas Erho, Paul L Nguyen, Elai Davicioni, Felix Y Feng
Department of Radiation Oncology, University of Michigan. , Department of Radiation Oncology, University of Michigan Medical School. , Pathology, University of Michigan. , Department of Radiation Oncology, University of Michigan. , Department of Radiation Oncology, University of Michigan. , Department of Radiation Oncology, University of Michigan. , James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions. , Urology, Johns Hopkins University. , Glickman Urological and Kidney Institute, Cleveland Clinic. , Radiation Oncology, Thomas Jefferson University. , Radiation Oncology, Thomas Jefferson Univ. , Urology, Mayo Clinic. , GenomeDx Biosciences Inc. , GenomeDx Biosciences Inc. , Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital. , GenomeDx Biosciences Inc. , GenomeDx Biosciences Inc. , Comprehensive Cancer Center, University of Michigan