title: Reduced activity of double-strand break repair genes in prostate cancer patients with late normal tissue radiation toxicity.
abstract: OBJECTIVE
  To investigate clinical parameters and DNA damage response as possible risk factors for radiation toxicity in the setting of prostate cancer.
  
  
  METHODS
  Clinical parameters of 61 prostate cancer patients, 34 with (overresponding, OR) and 27 without (non-responding, NR) severe late radiation toxicity were assembled. In addition, for a matched subset the DNA damage repair kinetics (γ-H2AX assay) and expression profiles of DNA repair genes were determined in ex vivo irradiated lymphocytes.
  
  
  RESULTS
  Examination of clinical data indicated none of the considered clinical parameters to be correlated with the susceptibility of patients to develop late radiation toxicity. Although frequencies of γ-H2AX foci induced immediately after irradiation were similar (P=.32), significantly higher numbers of γ-H2AX foci were found 24 hours after irradiation in OR compared with NR patients (P=.03). Patient-specific γ-H2AX foci decay ratios were significantly higher in NR patients than in OR patients (P<.0001). Consequently, NR patients seem to repair DNA double-strand breaks (DSBs) more efficiently than OR patients. Moreover, gene expression analysis indicated several genes of the homologous recombination pathway to be stronger induced in NR compared with OR patients (P<.05). A similar trend was observed in genes of the nonhomologous end-joining repair pathway (P=.09). This is congruent with more proficient repair of DNA DSBs in patients without late radiation toxicity.
  
  
  CONCLUSIONS
  Both gene expression profiling and DNA DSB repair kinetics data imply that less-efficient repair of radiation-induced DSBs may contribute to the development of late normal tissue damage. Induction levels of DSB repair genes (eg, RAD51) may potentially be used to assess the risk for late radiation toxicity.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: b.vanoorschot@amc.uva.nl.
authors.forename: Bregje
authors.initials: B
authors.lastname: van Oorschot
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Hovingh
authors.affiliation: Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Perry D
authors.initials: PD
authors.lastname: Moerland
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Lukas J A
authors.initials: LJ
authors.lastname: Stalpers
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Vrieling
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Nicolaas A P
authors.initials: NA
authors.lastname: Franken
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D058958:Organs at Risk / Q000528:radiation effects*; D010766:Phosphorylation; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000235:genetics* / Q000378:metabolism; D012007:Rectum / Q000378:metabolism / Q000528:radiation effects; D012307:Risk Factors; D001743:Urinary Bladder / Q000378:metabolism / Q000528:radiation effects
chemical_list: C468783:H2AX protein, human; D006657:Histones; D017430:Prostate-Specific Antigen