title: Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity.
abstract: OBJECTIVE
  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
  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).
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Adeline
authors: A
authors: Granzotto
authors: INSERM UMRS 1018, Institut Gustave-Roussy, Villejuif, France.
authors: Mohamed Amine
authors: MA
authors: Benadjaoud
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France; Institut de Cancérologie de Lorraine, Vandoeuvre-les-Nancy, France.
authors: Guillaume
authors: G
authors: Vogin
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Clément
authors: C
authors: Devic
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Mélanie L
authors: ML
authors: Ferlazzo
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France; Université Saint-Joseph, Beirut, Lebanon.
authors: Larry
authors: L
authors: Bodgi
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Sandrine
authors: S
authors: Pereira
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Laurène
authors: L
authors: Sonzogni
authors: Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France.
authors: Fabien
authors: F
authors: Forcheron
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Muriel
authors: M
authors: Viau
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Aurélie
authors: A
authors: Etaix
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Karim
authors: K
authors: Malek
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Laurence
authors: L
authors: Mengue-Bindjeme
authors: Centre de Biotechnologie Cellulaire et Biothèque, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
authors: Clémence
authors: C
authors: Escoffier
authors: Centre de Biotechnologie Cellulaire et Biothèque, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
authors: Isabelle
authors: I
authors: Rouvet
authors: Centre de Biotechnologie Cellulaire et Biothèque, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
authors: Marie-Thérèse
authors: MT
authors: Zabot
authors: Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France.
authors: Aurélie
authors: A
authors: Joubert
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Anne
authors: A
authors: Vincent
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Nicole
authors: N
authors: Dalla Venezia
authors: Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France.
authors: Michel
authors: M
authors: Bourguignon
authors: Clinique Jean-Mermoz, Lyon, France.
authors: Edme-Philippe
authors: EP
authors: Canat
authors: Groupement Hospitalier Sud, Hospices Civils de Lyon, Pierre-Bénite, France.
authors: Anne
authors: A
authors: d'Hombres
authors: Centre Hospitalier Universitaire, Nantes, France.
authors: Estelle
authors: E
authors: Thébaud
authors: Institut Curie, Paris, France.
authors: Daniel
authors: D
authors: Orbach
authors: Institut Curie, Paris, France.
authors: Dominique
authors: D
authors: Stoppa-Lyonnet
authors: Centre Joliot-Curie, Rouen, France.
authors: Abderraouf
authors: A
authors: Radji
authors: Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors: Eric
authors: E
authors: Doré
authors: Centre Hospitalier Régional Universitaire Bretonneau, Tours, France.
authors: Yoann
authors: Y
authors: Pointreau
authors: Institut du Val d'Aurelle, Montpellier, France.
authors: Céline
authors: C
authors: Bourgier
authors: Centre Oscar-Lambret, Lille, France.
authors: Pierre
authors: P
authors: Leblond
authors: Centre Oscar-Lambret, Lille, France.
authors: Anne-Sophie
authors: AS
authors: Defachelles
authors: Centre Oscar-Lambret, Lille, France.
authors: Cyril
authors: C
authors: Lervat
authors: Hôpital La Pitié-Salpétrière, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors: Stéphanie
authors: S
authors: Guey
authors: Hôpital La Pitié-Salpétrière, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors: Loic
authors: L
authors: Feuvret
authors: Hôpital Saint Joseph, Charleroi, Belgique.
authors: Françoise
authors: F
authors: Gilsoul
authors: Centre Hospitalier Universitaire, Saint-Etienne, France.
authors: Claire
authors: C
authors: Berger
authors: Centre Hospitalier Universitaire, Saint-Etienne, France.
authors: Coralie
authors: C
authors: Moncharmont
authors: Centre Hospitalier Universitaire, Saint-Etienne, France.
authors: Guy
authors: G
authors: de Laroche
authors: Institut de Cancérologie de Lorraine, Vandoeuvre-les-Nancy, France.
authors: Marie-Virginie
authors: MV
authors: Moreau-Claeys
authors: Institut Gustave-Roussy, Villejuif, France.
authors: Nicole
authors: N
authors: Chavaudra
authors: Centre Léon-Bérard, Lyon, France.
authors: Patrick
authors: P
authors: Combemale
authors: Centre Léon-Bérard, Lyon, France.
authors: Marie-Claude
authors: MC
authors: Biston
authors: Centre Léon-Bérard, Lyon, France.
authors: Claude
authors: C
authors: Malet
authors: Centre Léon-Bérard, Lyon, France.
authors: Isabelle
authors: I
authors: Martel-Lafay
authors: Centre Léon-Bérard, Lyon, France.
authors: Cécile
authors: C
authors: Laude
authors: Centre Léon-Bérard, Lyon, France; Centre Hospitalier Métropôle-Savoie, Chambéry, France.
authors: Ngoc-Hanh
authors: NH
authors: Hau-Desbat
authors: Centre Léon-Bérard, Lyon, France.
authors: Amira
authors: A
authors: Ziouéche
authors: Centre Léon-Bérard, Lyon, France.
authors: Ronan
authors: R
authors: Tanguy
authors: Centre Léon-Bérard, Lyon, France.
authors: Marie-Pierre
authors: MP
authors: Sunyach
authors: Centre Léon-Bérard, Lyon, France.
authors: Séverine
authors: S
authors: Racadot
authors: Centre Léon-Bérard, Lyon, France.
authors: Pascal
authors: P
authors: Pommier
authors: Centre Léon-Bérard, Lyon, France.
authors: Line
authors: L
authors: Claude
authors: Institut d'Hématologie et d'Oncologie Pédiatrique, Hospices Civils de Lyon, Lyon, France.
authors: Frédéric
authors: F
authors: Baleydier
authors: Centre Marie Curie, Valence, France.
authors: Bertrand
authors: B
authors: Fleury
authors: Centre Eugène-Marquis, Rennes, France.
authors: Renaud
authors: R
authors: de Crevoisier
authors: Hôpital La Pitié-Salpétrière, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors: Jean-Marc
authors: JM
authors: Simon
authors: Institut Curie, Paris, France; Centre Jean-Perrin, Clermont-Ferrand, France.
authors: Pierre
authors: P
authors: Verrelle
authors: Institut de Cancérologie de Lorraine, Vandoeuvre-les-Nancy, France.
authors: Didier
authors: D
authors: Peiffert
authors: Hôpital Henri-Mondor, Assistance Publique des Hôpitaux de Paris, Créteil, France.
authors: Yazid
authors: Y
authors: Belkacemi
authors: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors: Jean
authors: J
authors: Bourhis
authors: Centre Oscar-Lambret, Lille, France.
authors: Eric
authors: E
authors: Lartigau
authors: Centre Léon-Bérard, Lyon, France.
authors: Christian
authors: C
authors: Carrie
authors: Institut de Cancérologie de Lorraine, Vandoeuvre-les-Nancy, France.
authors: Florent
authors: F
authors: De Vathaire
authors: Institut Gustave-Roussy, Villejuif, France.
authors: François
authors: F
authors: Eschwege
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France.
authors: Alain
authors: A
authors: Puisieux
authors: Hôpital Henri-Mondor, Assistance Publique des Hôpitaux de Paris, Créteil, France.
authors: Jean-Léon
authors: JL
authors: Lagrange
authors: Centre Hospitalier Universitaire, Grenoble, France.
authors: Jacques
authors: J
authors: Balosso
authors: INSERM, UMR1052, Cancer Research Centre of Lyon, Lyon, France. Electronic address: Nicolas.foray@inserm.fr.
authors: Nicolas
authors: N
authors: Foray
mesh_terms: D000704:Analysis of Variance; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005347:Fibroblasts / Q000528:radiation effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015162:Micronucleus Tests / Q000379:methods; D010766:Phosphorylation; D011832:Radiation Injuries / Q000145:classification* / Q000378:metabolism / Q000473:pathology; D011836:Radiation Tolerance / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000473:pathology / Q000528:radiation effects*; D013997:Time Factors
chemical_list: C468783:H2AX protein, human; D006657:Histones; D064007:Ataxia Telangiectasia Mutated Proteins