Compromized DNA repair as a basis for identification of cancer radiotherapy patients with extreme radiosensitivity.
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.
Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia.
Pavel
P
Lobachevsky
The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia; Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia.
Trevor
T
Leong
Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia.
Patricia
P
Daly
Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia.
Jai
J
Smith
Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia.
Nickala
N
Best
Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia.
Jonathan
J
Tomaszewski
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia.
Ella R
ER
Thompson
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia; Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 13 Hang Kong Lu, Jianghan, Wuhan, Hubei, China.
Na
N
Li
The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia.
Ian G
IG
Campbell
Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia.
Roger F
RF
Martin
Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia; Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Australia. Electronic address: olga.martin@petermac.org.
Olga A
OA
Martin
D000328:Adult; D000368:Aged; D000465:Algorithms; D015415:Biomarkers / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D003661:Decision Support Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D018859:Hair Follicle / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D017711:Nonlinear Dynamics; D011832:Radiation Injuries / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011836:Radiation Tolerance; D011878:Radiotherapy / Q000009:adverse effects; D011879:Radiotherapy Dosage; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index
D015415:Biomarkers; C468783:H2AX protein, human; D006657:Histones; D045643:DNA Repair Enzymes
DNA repair; Predictive assays; Radiation therapy; Radiosensitivity; Statistical criteria; γ-H2AX
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