title: DNA-PKcs expression predicts response to radiotherapy in prostate cancer.
abstract: OBJECTIVE
  Double-strand breaks, the most lethal DNA lesions induced by ionizing radiation, are mainly repaired by the nonhomologous end-joining system. The expression of the nonhomologous end-joining pathway has never been studied in prostate cancer, and its prognostic value for patients undergoing radiotherapy remains unknown.
  
  
  METHODS
  Pretreatment biopsies from 238 patients treated with exclusive external beam radiotherapy for localized prostate cancer with ≥ 2 years of follow-up were reviewed to reassess the Gleason score. Of these 238 cases, 179 were suitable for in situ analysis and were included in the tissue microarrays. Expression of the nonhomologous end-joining proteins Ku70, Ku80, DNA-dependent protein kinase, catalytic subunits (DNA-PKcs), and X-ray repair cross complementing 4-like factor was studied by immunohistochemistry, together with the proliferation marker Ki67.
  
  
  RESULTS
  The predictive value of the Gleason score for biochemical relapse (using the Phoenix criteria) was markedly improved after review (P<.0001) compared with the initial score (P=.003). The clinical stage, pretreatment prostate-specific antigen level, and perineural invasion status were also associated with progression-free survival (P=.005, P<.0001, and P=.03, respectively). High proliferation (>4%) tends to be associated with biochemical recurrence; however, the difference did not reach statistical significance (P=.06). Although the expression of Ku70, Ku80, and X-ray repair cross complementing 4-like factor was not predictive of relapse, positive DNA-PKcs nuclear staining was closely associated with biochemical recurrence (P=.0002). On multivariate analysis, only the Gleason score, prostate-specific antigen level, and DNA-PKcs status remained predictive of recurrence (P=.003, P=.002, and P=.01, respectively).
  
  
  CONCLUSIONS
  The results of the present study highly suggest that DNA-PKcs could be a predictive marker of recurrence after radiotherapy, independently of the classic prognostic markers, including the Gleason score modified after review.
authors.affiliation: Department of Pathology, CHU-Universite de Poitiers, Poitiers, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bouchaert
authors.forename: Stephane
authors.initials: S
authors.lastname: Guerif
authors.forename: Celine
authors.initials: C
authors.lastname: Debiais
authors.forename: Jacques
authors.initials: J
authors.lastname: Irani
authors.forename: Gaelle
authors.initials: G
authors.lastname: Fromont
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D034961:Antigens, Nuclear / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D018572:Disease-Free Survival; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D000072200:Ku Autoantigen; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D011237:Predictive Value of Tests; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D046888:Tissue Array Analysis / Q000379:methods
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; C508551:NHEJ1 protein, human; D009363:Neoplasm Proteins; D051747:DNA-Activated Protein Kinase; D017430:Prostate-Specific Antigen; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D045643:DNA Repair Enzymes