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

Journal Article · Tue Mar 01 04:00:00 EST 2016 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/J.IJROBP.2015.11.013· OSTI ID:22645094

Granzotto, Adeline ^[1]; Benadjaoud, Mohamed Amine ^[2]; Vogin, Guillaume ^[1]; Devic, Clément; Ferlazzo, Mélanie L. ^[1]; Bodgi, Larry ^[1]; Pereira, Sandrine; Sonzogni, Laurène ^[1]; Forcheron, Fabien ^[3]; Viau, Muriel; Etaix, Aurélie; Malek, Karim; Mengue-Bindjeme, Laurence ^[1]; Escoffier, Clémence; Rouvet, Isabelle; Zabot, Marie-Thérèse ^[4]; Joubert, Aurélie ^[5]; Vincent, Anne; Venezia, Nicole Dalla ^[1]; Bourguignon, Michel ^[5] ; others, and

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1. INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon (France)
2. INSERM UMRS 1018, Institut Gustave-Roussy, Villejuif (France)
3. Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge (France)
4. Centre de Biotechnologie Cellulaire et Biothèque, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron (France)
5. Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses (France)

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).

• OSTI ID: 22645094
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 3 Vol. 94; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
DNA REPAIR
FLUORINE COMPOUNDS
GY RANGE 01-10
NEOPLASMS
PATIENTS
RADIOSENSITIVITY
RADIOTHERAPY
STRAND BREAKS