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

Adeline Granzotto 1 Mohamed Amine Benadjaoud 2 Guillaume Vogin 1 Clément Devic 1 Mélanie L. Ferlazzo 1 Larry Bodgi 1 Sandrine Pereira 3, 1 Laurène Sonzogni 1 Fabien Forcheron Muriel Viau 1 Aurélie Etaix Karim Malek 4, 1 Laurence Mengue-Bindjeme 1 Clémence Escoffier 5 Isabelle Rouvet 5 Marie-Therese Zabot 5 Aurélie Joubert Anne Vincent 1 Nicole Dalla Venezia 1 Michel Bourguignon Edme-Philippe Canat Anne d'Hombres Estelle Thébaud Daniel Orbach 6 Dominique Stoppa-Lyonnet 7 Abderraouf Radji Eric Doré 8 Yoann Pointreau 9 Céline Bourgier 10 Pierre Leblond Anne-Sophie Defachelles Cyril Lervat Stéphanie Guey Loic Feuvret 11 Françoise Gilsoul Claire Berger Coralie Moncharmont 12, 13 Guy Laroche Marie-Virginie Moreau-Claeys Nicole Chavaudra 14 Patrick Combemale 15, 16 Marie-Claude Biston 17, 18 Claude Malet 18 Isabelle Martel-Lafay 18 Cécile Laude 18 Ngoc-Hanh Hau-Desbat 18 Amira Ziouéche 18 Ronan Tanguy 18 Marie-Pierre Sunyach 18 Séverine Racadot 18 Pascal Pommier 18 Line Claude 18 Frédéric Baleydier 1, 19 Bertrand Fleury Renaud Crevoisier 20 Jean-Marc Simon 21 Pierre Verrelle 22 Didier Peiffert 23 Yazid Belkacemi 24 Jean Bourhis Eric Lartigau 25 Christian Carrie 18 Florent de Vathaire 23 François Eschwège 26 Alain Puisieux 1, 27 Jean-Léon Lagrange 28 Jacques Balosso 29 Nicolas Foray 1
3 Equipe2
UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
17 Imagerie Tomographique et Radiothérapie
CREATIS - Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé
Abstract : 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)
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Submitted on : Wednesday, February 17, 2016 - 4:22:24 PM
Last modification on : Wednesday, October 14, 2020 - 4:09:04 AM



Adeline Granzotto, Mohamed Amine Benadjaoud, Guillaume Vogin, Clément Devic, Mélanie L. Ferlazzo, et al.. Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity. International Journal of Radiation Oncology - Biology - Physics, Elsevier, 2016, 94 (3), pp.450--460. ⟨10.1016/j.ijrobp.2015.11.013⟩. ⟨hal-01275547⟩



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