title: The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer.
abstract: OBJECTIVE
  There is a clear need to improve risk stratification and to 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.
  
  
  METHODS
  We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13.4 years). 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.
  
  
  RESULTS
  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 signature, and CAPRA-S).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Transitional Year Program, Beaumont Hospital-Dearborn, Dearborn, Michigan.
authors.forename: Shuang G
authors.initials: SG
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Evans
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Vishal
authors.initials: V
authors.lastname: Kothari
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Grace
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Ashley
authors.initials: A
authors.lastname: Larm
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Victor
authors.initials: V
authors.lastname: Mondine
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schaeffer
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Ross
authors.affiliation: Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Klein
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: GenomeDx Biosciences Inc., Vancouver, British Columbia, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Nguyen
authors.affiliation: GenomeDx Biosciences Inc., Vancouver, British Columbia, Canada.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. ffeng@med.umich.edu.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
mesh_terms: D014408:Biomarkers, Tumor; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor