title: Patient-Level DNA Damage and Repair Pathway Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer.
abstract: OBJECTIVE
  A substantial number of patients diagnosed with high-risk prostate cancer are at risk for metastatic progression after primary treatment. Better biomarkers are needed to identify patients at the highest risk to guide therapy intensification.
  
  
  OBJECTIVE
  To create a DNA damage and repair (DDR) pathway profiling method for use as a prognostic signature biomarker in high-risk prostate cancer.
  
  
  METHODS
  A cohort of 1090 patients with high-risk prostate cancer who underwent prostatectomy and were treated at 3 different academic institutions were divided into a training cohort (n = 545) and 3 pooled validation cohorts (n = 232, 130, and 183) assembled for case-control or case-cohort studies. Profiling of 9 DDR pathways using 17 gene sets for GSEA (Gene Set Enrichment Analysis) of high-density microarray gene expression data from formalin-fixed paraffin-embedded prostatectomy samples with median 10.3 years follow-up was performed. Prognostic signature development from DDR pathway profiles was studied, and DDR pathway gene mutation in published cohorts was analyzed.
  
  
  METHODS
  Biochemical recurrence-free, metastasis-free, and overall survival.
  
  
  RESULTS
  Across the training cohort and pooled validation cohorts, 1090 men were studied; mean (SD) age at diagnosis was 65.3 (6.4) years. We found that there are distinct clusters of DDR pathways within the cohort, and DDR pathway enrichment is only weakly correlated with clinical variables such as age (Spearman ρ [ρ], range, -0.07 to 0.24), Gleason score (ρ, range, 0.03 to 0.20), prostate-specific antigen level (ρ, range, -0.07 to 0.10), while 13 of 17 DDR gene sets are strongly correlated with androgen receptor pathway enrichment (ρ, range, 0.33 to 0.82). In published cohorts, DDR pathway genes are rarely mutated. A DDR pathway profile prognostic signature built in the training cohort was significantly associated with biochemical recurrence-free, metastasis-free, and overall survival in the pooled validation cohorts independent of standard clinicopathological variables. The prognostic performance of the signature for metastasis-free survival appears to be stronger in the younger patients (HR, 1.67; 95% CI, 1.12-2.50) than in the older patients (HR, 0.77; 95% CI, 0.29-2.07) on multivariate Cox analysis.
  
  
  CONCLUSIONS
  DNA damage and repair pathway profiling revealed patient-level variations and the DDR pathways are rarely affected by mutation. A DDR pathway signature showed strong prognostic performance with the long-term outcomes of metastasis-free and overall survival that may be useful for risk stratification of high-risk prostate cancer patients.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Evans
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor2Beaumont Hospital - Dearborn, Transitional Year Program, Dearborn, Michigan.
authors.forename: Shuang G
authors.initials: SG
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor.
authors.forename: S Laura
authors.initials: SL
authors.lastname: Chang
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: GenomeDx Biosciences Inc, Vancouver, British Columbia, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and New York Presbyterian Hospitals, New York, New York.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.affiliation: Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schiewer
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Spratt
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor.
authors.forename: Vishal
authors.initials: V
authors.lastname: Kothari
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, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
authors.affiliation: Department of Radiation Oncology, Jefferson 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: City of Hope, Duarte, California.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Yu
authors.affiliation: Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Nguyen
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and New York Presbyterian Hospitals, New York, New York.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.affiliation: Drug Development Unit and Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, England.
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.affiliation: Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
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 Arbor13Michigan Center for Translational Pathology, University of Michigan, Ann Arbor14Comprehensive Cancer Center, University of Michigan, Ann Arbor.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D012189:Retrospective Studies; D012307:Risk Factors; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor