title: Repair of ionizing radiation-induced DNA damage and risk of second cancer in childhood cancer survivors.
abstract: The study's purpose was to assess whether individuals who developed a second malignant neoplasm (SMN) after treatment for a first malignant neoplasm (FMN) had a lower ability to repair DNA double-strand breaks (DSBs) using a bioassay with γH2AX intensity as a surrogate endpoint. In a case-control study nested in a cohort of childhood cancer survivors, lymphoblastoid cell lines (LCLs) were established from blood samples collected from 94 cases (SMN) and 94 matched controls (FMN). LCLs were irradiated with ionizing radiation (2 and 5 Gy) and γH2AX intensities measured 1, 3, 5 and 24h post-irradiation. Differences in mean γH2AX intensity between cases and controls were compared using Kruskal-Wallis tests. Generalized linear models for repeated measures and conditional logistic regressions for SMN risk estimates were performed. The mean baseline γH2AX intensity measured without irradiation was 9.1 [95% confidence interval (95% CI): 8.5-9.7] in the LCLs from cases and 6.4 (95% CI: 6.0-6.8) from controls (P < 0.001). Markedly higher γH2AX intensity, particularly at 1 h post-irradiation, was also found in the LCLs from the cases compared with the controls for all FMNs and for different types of FMN. Chemotherapy and radiation doses received by bone marrow and thymus for FMN treatment showed a non-significant effect on γH2AX intensity. This case-control study shows that higher baseline and post-irradiation levels of DNA DSBs, as measured by γH2AX intensity, are associated with the risk of SMN in childhood cancer survivors. Further investigations in a prospective setting are warranted to confirm this association.
authors.forename: Nadia
authors.initials: N
authors.lastname: Haddy
authors.affiliation: Institut Curie-Recherche, Bats 110-112, 91405 Orsay, France, INSERM U612, Institut Curie, Bats 110-112, 91405 Orsay, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Tartier
authors.forename: Serge
authors.initials: S
authors.lastname: Koscielny
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Adjadj
authors.forename: Carole
authors.initials: C
authors.lastname: Rubino
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugières
authors.affiliation: Institut Curie, 75005 Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Pacquement
authors.forename: Ibrahima
authors.initials: I
authors.lastname: Diallo
authors.forename: Florent
authors.initials: F
authors.lastname: de Vathaire
authors.affiliation: Institut Curie-Recherche, Bats 110-112, 91405 Orsay, France.
authors.forename: Dietrich
authors.initials: D
authors.lastname: Averbeck
authors.affiliation: Institut Curie-Recherche, Bats 110-112, 91405 Orsay, France, INSERM U612, Institut Curie, Bats 110-112, 91405 Orsay, France.
authors.forename: Janet
authors.initials: J
authors.lastname: Hall
authors.affiliation: INSERM U946, Fondation Jean Dausset, 75010 Paris, France and CNRS UMR8200, Institut Gustave Roussy, 94805 Villejuif, France simone.benhamou@inserm.fr.
authors.forename: Simone
authors.initials: S
authors.lastname: Benhamou
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006657:Histones / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009367:Neoplasm Staging; D009381:Neoplasms, Radiation-Induced / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality; D016609:Neoplasms, Second Primary / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality; D011379:Prognosis; D011839:Radiation, Ionizing; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D017741:Survivors; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: C468783:H2AX protein, human; D006657:Histones