TY - JOUR
T1 - Prostate Cancer Patients with Late Radiation Toxicity Exhibit Reduced Expression of Genes Involved in DNA Double-Strand Break Repair and Homologous Recombination
AU - van Oorschot, Bregje
AU - Uitterhoeve, Lon
AU - Oomen, Ilja
AU - ten Cate, Rosemarie
AU - Medema, Jan Paul
AU - Vrieling, Harry
AU - Stalpers, Lukas J. A.
AU - Moerland, Perry D.
AU - Franken, Nicolaas A. P.
PY - 2017
Y1 - 2017
N2 - Severe late damage to normal tissue is a major limitation of cancer radiotherapy in prostate cancer patients. In a recent retrospective study, late radiation toxicity was found to relate to a decreased decay of gamma-H2AX foci and reduced induction of DNA double-strand break repair genes. Here, we report evidence of prognostic utility in prostate cancer for gamma-H2AX foci decay ratios and gene expression profiles derived from ex vivoirradiated patient lymphocytes. Patients were followed >= 2 years after radiotherapy. Clinical characteristics were assembled, and toxicity was recorded using the Common Terminology Criteria (CTCAE) v4.0. No clinical factor was correlated with late radiation toxicity. The gamma-H2AX foci decay ratio correlated negatively with toxicity grade, with a significant difference between grade >= 3 and grade 0 patients (P =0.02). A threshold foci decay ratio, determined in our retrospective study, correctly classified 23 of 28 patients with grade >= 3 toxicity (sensitivity 82%) and 9 of 14 patients with grade 0 toxicity (specificity 64%). Induction of homologous recombination (HR) repair genes was reduced with increasing toxicity grade. The difference in fold induction of the HR gene set was most pronounced between grade 0 and grade >= 3 toxicity (P = 0.008). Notably, reduced responsiveness of HR repair genes to irradiation and inefficient double-strand break repair correlated with severe late radiation toxicity. Using a decay ratio classifier, we correctly classified 82% of patients with grade >= 3 toxicity, suggesting a prognostic biomarker for cancer patients with a genetically enhanced risk for late radiation toxicity to normal tissues after radiotherapy. (C)2017 AACR
AB - Severe late damage to normal tissue is a major limitation of cancer radiotherapy in prostate cancer patients. In a recent retrospective study, late radiation toxicity was found to relate to a decreased decay of gamma-H2AX foci and reduced induction of DNA double-strand break repair genes. Here, we report evidence of prognostic utility in prostate cancer for gamma-H2AX foci decay ratios and gene expression profiles derived from ex vivoirradiated patient lymphocytes. Patients were followed >= 2 years after radiotherapy. Clinical characteristics were assembled, and toxicity was recorded using the Common Terminology Criteria (CTCAE) v4.0. No clinical factor was correlated with late radiation toxicity. The gamma-H2AX foci decay ratio correlated negatively with toxicity grade, with a significant difference between grade >= 3 and grade 0 patients (P =0.02). A threshold foci decay ratio, determined in our retrospective study, correctly classified 23 of 28 patients with grade >= 3 toxicity (sensitivity 82%) and 9 of 14 patients with grade 0 toxicity (specificity 64%). Induction of homologous recombination (HR) repair genes was reduced with increasing toxicity grade. The difference in fold induction of the HR gene set was most pronounced between grade 0 and grade >= 3 toxicity (P = 0.008). Notably, reduced responsiveness of HR repair genes to irradiation and inefficient double-strand break repair correlated with severe late radiation toxicity. Using a decay ratio classifier, we correctly classified 82% of patients with grade >= 3 toxicity, suggesting a prognostic biomarker for cancer patients with a genetically enhanced risk for late radiation toxicity to normal tissues after radiotherapy. (C)2017 AACR
U2 - https://doi.org/10.1158/0008-5472.CAN-16-1966
DO - https://doi.org/10.1158/0008-5472.CAN-16-1966
M3 - Article
C2 - 28108515
SN - 0008-5472
VL - 77
SP - 1485
EP - 1491
JO - Cancer research
JF - Cancer research
IS - 6
ER -