title: Genetic factors in individual radiation sensitivity.
abstract: Cancer risk and radiation sensitivity are often associated with alterations in DNA repair, cell cycle, or apoptotic pathways. Interindividual variability in mutagen or radiation sensitivity and in cancer susceptibility may also be traced back to polymorphisms of genes affecting e.g. DNA repair capacity. We studied possible associations between 70 polymorphisms of 12 DNA repair genes with basal and initial DNA damage and with repair thereof. We investigated DNA damage induced by ionizing radiation in lymphocytes isolated from 177 young lung cancer patients and 169 cancer-free controls. We also sought replication of our findings in an independent sample of 175 families (in total 798 individuals). DNA damage was assessed by the Olive tail moment (OTM) of the comet assay. DNA repair capacity (DRC) was determined for 10, 30 and, 60min of repair. Genes involved in the single-strand-repair pathway (SSR; like XRCC1 and MSH2) as well as genes involved in the double-strand-repair pathway (DSR; like RAD50, XRCC4, MRE11 and ATM) were found to be associated with DNA damage. The most significant association was observed for marker rs3213334 (p=0.005) of XRCC1 with basal DNA damage (B), in both cases and controls. A clear additive effect on the logarithm of OTM was identified for the marker rs1001581 of the same LD-block (p=0.039): BCC=-1.06 (95%-CI: -1.16 to -0.96), BCT=-1.02 (95%-CI: -1.11 to -0.93) and BTT=-0.85 (95%-CI: -1.01 to -0.68). In both cases and controls, we observed significantly higher DNA basal damage (p=0.007) for carriers of the genotype AA of marker rs2237060 of RAD50 (involved in DSR). However, this could not be replicated in the sample of families (p=0.781). An alteration to DRC after 30min of repair with respect to cases was observed as borderline significant for marker rs611646 of ATM (involved in DSR; p=0.055), but was the most significant finding in the sample of families (p=0.009). Our data indicate that gene variation impacts measurably on DNA damage and repair, suggesting at least a partial contribution to radiation sensitivity and lung cancer susceptibility.
authors.affiliation: Department of Radiation Protection and Health, Federal Office for Radiation Protection, Ingolstaedter Landstr.1, 85764 Oberschleissheim,Germany. Electronic address: shornhardt@bfs.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hornhardt
authors.affiliation: Department of Radiation Protection and Health, Federal Office for Radiation Protection, Ingolstaedter Landstr.1, 85764 Oberschleissheim,Germany. Electronic address: uroessler@bfs.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Rößler
authors.affiliation: Institute of Epidemiology, Helmholtz Center Munich, 85764 Neuherberg, Germany. Electronic address: wiebke.sauter@boehringer-ingelheim.com.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Sauter
authors.affiliation: Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany. Electronic address: arosenb@gwdg.de.
authors.forename: Albert
authors.initials: A
authors.lastname: Rosenberger
authors.affiliation: Institute of Epidemiology, Helmholtz Center Munich, 85764 Neuherberg, Germany. Electronic address: illig.thomas@mh-hannover.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.affiliation: Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany. Electronic address: hbickeb@gwdg.de.
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.affiliation: Institute of Epidemiology, Helmholtz Center Munich, 85764 Neuherberg, Germany; Department of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University Munich, 80539 Munich, Germany. Electronic address: wichmann@helmholtz-muenchen.de.
authors.forename: Hans-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.affiliation: Department of Radiation Protection and Health, Federal Office for Radiation Protection, Ingolstaedter Landstr.1, 85764 Oberschleissheim,Germany. Electronic address: mgomolka@bfs.de.
authors.forename: Maria
authors.initials: M
authors.lastname: Gomolka
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair / Q000528:radiation effects; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011836:Radiation Tolerance / Q000235:genetics*; D055815:Young Adult
keywords: DNA damage; DNA repair; DNA repair pathways; Polymorphisms; Radiation sensitivity