Reduced Activity of Double-Strand Break Repair Genes in Prostate Cancer Patients With Late Normal Tissue Radiation Toxicity

• Published in: International journal of radiation oncology, biology, physics Vol. 88; no. 3; pp. 664 - 670
• Main Authors: van Oorschot, Bregje, MSc, Hovingh, Suzanne E., MSc, Moerland, Perry D., PhD, Medema, Jan Paul, PhD, Stalpers, Lukas J.A., MD, PhD, Vrieling, Harry, PhD, Franken, Nicolaas A.P., PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2014
• Subjects: Aged; Aged, 80 and over; BIOLOGICAL PATHWAYS; COMPARATIVE EVALUATIONS; DNA; DNA Breaks, Double-Stranded; DNA REPAIR; DNA Repair - genetics; Gene Expression Profiling - methods; GENE RECOMBINATION; GENES; Hematology, Oncology and Palliative Medicine; Histones - metabolism; Humans; LYMPHOCYTES; Lymphocytes - radiation effects; Male; Middle Aged; NEOPLASMS; Organs at Risk - radiation effects; PATIENTS; Phosphorylation; PROSTATE; Prostate-Specific Antigen - blood; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - radiotherapy; Radiation Injuries - genetics; Radiation Injuries - metabolism; Radiology; RADIOLOGY AND NUCLEAR MEDICINE; Rectum - metabolism; Rectum - radiation effects; Risk Factors; STRAND BREAKS; TOXICITY; Urinary Bladder - metabolism; Urinary Bladder - radiation effects
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2013.11.219

Purpose To investigate clinical parameters and DNA damage response as possible risk factors for radiation toxicity in the setting of prostate cancer. Methods and Materials 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.