title: High-throughput transcriptomic analysis nominates proteasomal genes as age-specific biomarkers and therapeutic targets in prostate cancer.
abstract: BACKGROUND
  Although prostate cancer (PCa) is hypothesized to differ in nature between younger versus older patients, the underlying molecular distinctions are poorly understood. We hypothesized that high-throughput transcriptomic analysis would elucidate biological differences in PCas arising in younger versus older men, and would nominate potential age-specific biomarkers and therapeutic targets.
  
  
  METHODS
  The high-density Affymetrix GeneChip platform, encompassing >1 million genomic loci, was utilized to assess gene expression in 1090 radical prostatectomy samples from patients with long-term follow-up. We identified genes associated with metastatic progression by 10 years post-treatment in younger (age<65) versus older (age⩾65) patients, and ranked these genes by their prognostic value. We performed Gene Set Enrichment Analysis (GSEA) to nominate biological concepts that demonstrated age-specific effects, and validated a target by treating with a clinically available drug in three PCa cell lines derived from younger men.
  
  
  RESULTS
  Over 80% of the top 1000 prognostic genes in younger and older men were specific to that age group. GSEA nominated the proteasome pathway as the most differentially prognostic in younger versus older patients. High expression of proteasomal genes conferred worse prognosis in younger but not older men on univariate and multivariate analysis. Bortezomib, a Food and Drug Administration approved proteasome inhibitor, decreased proliferation in three PCa cell lines derived from younger patients.
  
  
  CONCLUSIONS
  Our data show significant global differences in prognostic genes between older versus younger men. We nominate proteasomeal gene expression as an age-specific biomarker and potential therapeutic target specifically in younger men. Limitations of our study include clinical differences between cohorts, and increased comorbidities and lower survival in older patients. These intriguing findings suggest that current models of PCa biology do not adequately represent genetic heterogeneity of PCa related to age, and future clinical trials would benefit from stratification based on age.
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Jackson
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: V
authors.initials: V
authors.lastname: Kothari
authors.affiliation: 1] Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Biostatistics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Schipper
authors.affiliation: GenomeDx Biosciences Inc., Vancouver, British Columbia, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Erho
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Evans
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: C
authors.initials: C
authors.lastname: Speers
authors.affiliation: 1] Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Hamstra
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Y S
authors.initials: YS
authors.lastname: Niknafs
authors.affiliation: Department of Radiation Oncology, Harvard University, Boston, MA, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Nguyen
authors.affiliation: Departments of Urology, Oncology, and Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Schaeffer
authors.affiliation: Departments of Urology, Oncology, and Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Ross
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Den
authors.affiliation: Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Klein
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MI, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: GenomeDx Biosciences Inc., Vancouver, British Columbia, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: 1] Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA [3] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: F Y
authors.initials: FY
authors.lastname: Feng
mesh_terms: D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex