title: TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy: implications for fusion status and DSB repair.
abstract: BACKGROUND
  Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT).
  
  
  METHODS
  Pretreatment biopsies from two cohorts of patients with intermediate-risk prostate cancer [T1/T2, Gleason score (GS) < 8, prostate-specific antigen (PSA) < 20 ng/mL; >7 years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA samples assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion; and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy samples were scored within a defined tissue microarray (TMA) immunostained for ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir + 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model.
  
  
  RESULTS
  TMPRSS2-ERG fusion by aCGH was identified in 27 (21%) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50%) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis.
  
  
  CONCLUSIONS
  In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology and Biostatistics, University of Toronto; Radiation Medicine Program, Princess Margaret Hospital, University Health Network; Informatics and Bio-Computing Platform, Ontario Institute for Cancer Research, Toronto, Ontario; Department of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre; Laboratory for Advanced Genome Analysis - Vancouver Prostate Centre, Vancouver, British Columbia; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland; Division of Urology, University of Montreal Health Center, Montreal, Quebec; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario; and Department of Pathology and Laboratory Medicine and Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Dal Pra
authors.forename: Emilie
authors.initials: E
authors.lastname: Lalonde
authors.forename: Jenna
authors.initials: J
authors.lastname: Sykes
authors.forename: Fiona
authors.initials: F
authors.lastname: Warde
authors.forename: Adrian
authors.initials: A
authors.lastname: Ishkanian
authors.forename: Alice
authors.initials: A
authors.lastname: Meng
authors.forename: Chad
authors.initials: C
authors.lastname: Maloff
authors.forename: John
authors.initials: J
authors.lastname: Srigley
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Joshua
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Petrovics
authors.forename: Theodorus
authors.initials: T
authors.lastname: van der Kwast
authors.forename: Andrew
authors.initials: A
authors.lastname: Evans
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Colin
authors.initials: C
authors.lastname: Collins
authors.forename: Jeremy
authors.initials: J
authors.lastname: Squire
authors.forename: Wan
authors.initials: W
authors.lastname: Lam
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
mesh_terms: D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D004260:DNA Repair / Q000235:genetics*; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D061089:Radiotherapy, Image-Guided; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human