Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity

Purpose Whereas post–radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against diff...

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Veröffentlicht in:	International journal of radiation oncology, biology, physics biology, physics, 2016-03, Vol.94 (3), p.450-460
Hauptverfasser:	Granzotto, Adeline, BSc, Benadjaoud, Mohamed Amine, PhD, Vogin, Guillaume, MD, PhD, Devic, Clément, MSc, Ferlazzo, Mélanie L., MSc, Bodgi, Larry, PhD, Pereira, Sandrine, PhD, Sonzogni, Laurène, BSc, Forcheron, Fabien, PhD, Viau, Muriel, PhD, Etaix, Aurélie, PharmaD, Malek, Karim, MD, PhD, Mengue-Bindjeme, Laurence, MD, MSc, Escoffier, Clémence, MSc, Rouvet, Isabelle, PharmD, PhD, Zabot, Marie-Thérèse, PhD, Joubert, Aurélie, PhD, Vincent, Anne, PhD, Venezia, Nicole Dalla, PhD, Bourguignon, Michel, MD, PhD, Canat, Edme-Philippe, MD, d'Hombres, Anne, MD, Thébaud, Estelle, MD, Orbach, Daniel, MD, Stoppa-Lyonnet, Dominique, MD, PhD, Radji, Abderraouf, MD, Doré, Eric, MD, Pointreau, Yoann, MD, Bourgier, Céline, MD, PhD, Leblond, Pierre, MD, PhD, Defachelles, Anne-Sophie, MD, Lervat, Cyril, MD, Guey, Stéphanie, MD, Feuvret, Loic, MD, Gilsoul, Françoise, MD, Berger, Claire, MD, Moncharmont, Coralie, MD, de Laroche, Guy, MD, Moreau-Claeys, Marie-Virginie, MD, Chavaudra, Nicole, PhD, Combemale, Patrick, MD, Biston, Marie-Claude, PhD, Malet, Claude, PhD, Martel-Lafay, Isabelle, MD, Laude, Cécile, MD, Hau-Desbat, Ngoc-Hanh, MD, Ziouéche, Amira, MD, Tanguy, Ronan, MD, Sunyach, Marie-Pierre, MD, Racadot, Séverine, MD, Pommier, Pascal, MD, PhD, Claude, Line, MD, Baleydier, Frédéric, MD, PhD, Fleury, Bertrand, MD, de Crevoisier, Renaud, MD, PhD, Simon, Jean-Marc, MD, PhD, Verrelle, Pierre, MD, PhD, Peiffert, Didier, MD, PhD, Belkacemi, Yazid, MD, PhD, Bourhis, Jean, MD, PhD, Lartigau, Eric, MD, PhD, Carrie, Christian, MD, De Vathaire, Florent, PhD, Eschwege, François, MD, PhD, Puisieux, Alain, PharmD, PhD, Lagrange, Jean-Léon, MD, PhD, Balosso, Jacques, MD, PhD, Foray, Nicolas, PhD
Format:	Artikel
Sprache:	eng
Schlagworte:	Analysis of Variance Ataxia Telangiectasia Mutated Proteins - genetics Ataxia Telangiectasia Mutated Proteins - metabolism Bioengineering Biopsy Cell Line Cell Nucleus - metabolism DNA Breaks, Double-Stranded DNA REPAIR Fibroblasts - radiation effects FLUORINE COMPOUNDS GY RANGE 01-10 Hematology, Oncology and Palliative Medicine Histones - metabolism Humans Life Sciences Medical Physics Micronucleus Tests - methods NEOPLASMS PATIENTS Phosphorylation Physics Radiation Injuries - classification Radiation Injuries - metabolism Radiation Injuries - pathology Radiation Tolerance - genetics Radiation Tolerance - physiology Radiology RADIOLOGY AND NUCLEAR MEDICINE RADIOSENSITIVITY RADIOTHERAPY Skin - pathology Skin - radiation effects STRAND BREAKS Time Factors
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Zusammenfassung:	Purpose Whereas post–radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. Methods and Materials Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. Results OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. Conclusions Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).
ISSN:	0360-3016 1879-355X
DOI:	10.1016/j.ijrobp.2015.11.013