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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 6 Anne Vincent 1 Nicole Dalla Venezia 1 Michel Bourguignon 6 Edme-Philippe Canat Anne d'Hombres Estelle Thébaud Daniel Orbach 7 Dominique Stoppa-Lyonnet 8 Abderraouf Radji Eric Doré 9 Yoann Pointreau 10 Céline Bourgier 11 Pierre Leblond Anne-Sophie Defachelles Cyril Lervat Stéphanie Guey Loic Feuvret 12 Françoise Gilsoul Claire Berger Coralie Moncharmont 13, 14 Guy Laroche Marie-Virginie Moreau-Claeys Nicole Chavaudra 15 Patrick Combemale 16, 17 Marie-Claude Biston 18, 19 Claude Malet 19 Isabelle Martel-Lafay 19 Cécile Laude 19 Ngoc-Hanh Hau-Desbat 19 Amira Ziouéche 19 Ronan Tanguy 19 Marie-Pierre Sunyach 19 Séverine Racadot 19 Pascal Pommier 19 Line Claude 19 Frédéric Baleydier 1, 20 Bertrand Fleury Renaud Crevoisier 21 Jean-Marc Simon 22 Pierre Verrelle 23 Didier Peiffert 24 Yazid Belkacemi 25 Jean Bourhis Eric Lartigau 26 Christian Carrie 19 Florent de Vathaire 24 François Eschwège 27 Alain Puisieux 1, 28 Jean-Léon Lagrange 29 Jacques Balosso 30 Nicolas Foray 1
3 Equipe2
UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
18 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 : Tuesday, January 11, 2022 - 5:56:09 PM



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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