Compromized DNA repair as a basis for identification of cancer radiotherapy patients with extreme radiosensitivity.

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.

• Authors: Pavel Lobachevsky, Trevor Leong, Patricia Daly, Jai Smith, Nickala Best, Jonathan Tomaszewski, Ella R Thompson, Na Li, Ian G Campbell, Roger F Martin, Olga A Martin
• Journal: Cancer letters (Cancer Lett) Vol. 383 Issue 2 Pg. 212-219 (12 28 2016) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 27693457 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Biomarkers
• H2AX protein, human
• Histones
• DNA Repair Enzymes

Topics

• Adult
• Aged
• Algorithms
• Biomarkers (metabolism)
• DNA Repair (genetics)
• DNA Repair Enzymes (genetics, metabolism)
• Decision Support Techniques
• Dose-Response Relationship, Drug
• Female
• Hair Follicle (metabolism, pathology, radiation effects)
• Histones (metabolism)
• Humans
• Kinetics
• Lymphocytes (metabolism, pathology, radiation effects)
• Male
• Middle Aged
• Mutation
• Neoplasms (genetics, metabolism, pathology, radiotherapy)
• Nonlinear Dynamics
• Radiation Injuries (etiology, genetics, metabolism, pathology)
• Radiation Tolerance
• Radiotherapy (adverse effects)
• Radiotherapy Dosage
• Retrospective Studies
• Risk Assessment
• Risk Factors
• Severity of Illness Index