Compromized DNA repair as a basis for identification of cancer radiotherapy patients with extreme radiosensitivity. Issue 2 (28th December 2016)

• Record Type: Journal Article
• Authors: Lobachevsky, Pavel; Leong, Trevor; Daly, Patricia; Smith, Jai; Best, Nickala; Tomaszewski, Jonathan; Thompson, Ella R.; Li, Na; Campbell, Ian G.; Martin, Roger F.; Martin, Olga A.
• Is Part Of: Cancer letters. Volume 383:Issue 2(2016)
• Page Start: 212
• Page End: 219
• Publication Date: 2016-12-28
• Subjects: Radiation therapy -- Radiosensitivity -- Predictive assays -- DNA repair -- γ-H2AX -- Statistical criteria; RT radiation therapy -- RS radiosensitivity -- γ-H2AX phosphorylated histone H2AX -- 53BP1 p53 binding protein 1 -- DSB double-strand break -- PBL peripheral blood lymphocytes -- OR over-responders -- NOR not-over-responders -- PMCC Peter Maccallum Cancer Centre -- ROC receiver operating characteristics -- RTOG Radiation Therapy Oncology Group -- AUC area under the ROC curve -- FBS foetal bovine serum -- EDTA ethylenediaminetetraacetic acid -- PBS phosphate buffered saline -- N(t) number of foci at time t -- NM maximum foci number -- R repair rate -- Q fraction of unrepairable component -- LoF loss of function -- ess essential splice site mutations -- ExAC Exome Aggregation Consortium; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.09.010
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: A small percentage of cancer radiotherapy patients develop abnormally severe side effects as a consequence of intrinsic radiosensitivity. We analysed the γ-H2AX response to ex-vivo irradiation of peripheral blood lymphocytes (PBL) and plucked eyebrow hair follicles from 16 patients who developed severe late radiation toxicity following radiotherapy, and 12 matched control patients. Longer retention of the γ-H2AX signal and lower colocalization efficiency of repair factors in over-responding patients confirmed that DNA repair in these individuals was compromised. Five of the radiosensitive patients harboured LoF mutations in DNA repair genes. An extensive range of quantitative parameters of the γ-H2AX response were studied with the objective to establish a predictor for radiosensitivity status. The most powerful predictor was the combination of the fraction of the unrepairable component of γ-H2AX foci and repair rate in PBL, both derived from non-linear regression analysis of foci repair kinetics. We introduce a visual representation of radiosensitivity status that allocates a position for each patient on a two-dimensional "radiosensitivity map". This analytical approach provides the basis for larger prospective studies to further refine the algorithm, ultimately to triage capability. Highlights: Every patient responds to radiotherapy in individual manner. Some suffer severe side-effects because of their intrinsic radiosensitivity. γ-H2AX assay can detect such patients. "RS map" allows judging radiosensitivity, based on post-irradiation γ-H2AX kinetics.