Genetic factors in individual radiation sensitivity |
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| Affiliation: | 1. Department of Radiation Protection and Health, Federal Office for Radiation Protection, Ingolstaedter Landstr.1, 85764 Oberschleissheim,Germany;2. Institute of Epidemiology, Helmholtz Center Munich, 85764 Neuherberg, Germany;3. Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany;4. Department of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians—University Munich, 80539 Munich, Germany;1. The Clatterbridge Cancer Centre, Wirral, UK;2. Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK;1. The Institute of Cancer Research, London, UK;2. Royal Marsden NHS Foundation Trust, London, UK;3. Clatterbridge Centre for Oncology, Bebington, UK;1. Ryazan State Medical University named after academician IP Pavlov, Visokovoltnaya St. 9, Ryazan 390026, Russia;2. RUDN University, Miklukho–Maklai St. 6, Moscow 117198, Russia;3. Laboratory of Physicochemical and Ecological Pathophysiology, Institute of General Pathology and Pathophysiology, Baltiyskaya St. 8, Moscow 125315, Russia;4. Department of Biochemistry, Orenburg State Medical University, Sovetskaya St. 6, Orenburg 460000, Russia;5. Department of Biochemistry, South Ural State Medical University, Vorovskogo St. 64, Chelyabinsk, 454048, Russia;6. Laboratory of Biotechnology and Applied Bioelementology, Yaroslavl State University, Sovetskaya St. 14, Yaroslavl, 150000, Russia;7. All-Russian Research Institute of Medicinal and Aromatic Plants (VILAR), Grina St. 7, Moscow, 117216, Russia;8. Institute of Bioelementology (Russian Satellite Centre of Trace Element—Institute for UNESCO), Orenburg State University, Pobedy Ave. 13, Orenburg 460352, Russia;1. Radiation Oncology, Mission Regional Medical Center, Mission Viejo, CA;2. Thoracic Surgery, Mission Regional Medical Center, Mission Viejo, CA;3. Interventional Radiology, Mission Regional Medical Center, Mission Viejo, CA;1. Department of Radiation Oncology, Centre hospitalier de l''Universiténde Montréal (CHUM), Hôpital Notre-Dame, Montreal, Canada;2. CRCHUM-Centre de recherche du Centre Hospitalier de l''Universiténde Montréal, Quebec, Canada |
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| 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, 60 min 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 30 min 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. |
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| Keywords: | DNA damage DNA repair Radiation sensitivity DNA repair pathways Polymorphisms OTM" },{" #name" :" keyword" ," $" :{" id" :" kw0035" }," $$" :[{" #name" :" text" ," _" :" Olive tail moment %tail-DNA" },{" #name" :" keyword" ," $" :{" id" :" kw0045" }," $$" :[{" #name" :" text" ," _" :" percent DNA in the tail DRC" },{" #name" :" keyword" ," $" :{" id" :" kw0055" }," $$" :[{" #name" :" text" ," _" :" DNA repair capacity DMSO" },{" #name" :" keyword" ," $" :{" id" :" kw0065" }," $$" :[{" #name" :" text" ," _" :" dimethylsulfoxide PBS" },{" #name" :" keyword" ," $" :{" id" :" kw0075" }," $$" :[{" #name" :" text" ," _" :" phosphate-buffered saline PBSF" },{" #name" :" keyword" ," $" :{" id" :" kw0085" }," $$" :[{" #name" :" text" ," _" :" phosphate-buffered saline supplemented with 1% fetal calf serum FCS" },{" #name" :" keyword" ," $" :{" id" :" kw0095" }," $$" :[{" #name" :" text" ," _" :" fetal calf serum TE" },{" #name" :" keyword" ," $" :{" id" :" kw0105" }," $$" :[{" #name" :" text" ," _" :" tris-EDTA buffer EDTA" },{" #name" :" keyword" ," $" :{" id" :" kw0115" }," $$" :[{" #name" :" text" ," _" :" ethylenediamine-N,N,N’,N’-tetraacetic acid SLS" },{" #name" :" keyword" ," $" :{" id" :" kw0125" }," $$" :[{" #name" :" text" ," _" :" sodium lauryl sulfate LD" },{" #name" :" keyword" ," $" :{" id" :" kw0135" }," $$" :[{" #name" :" text" ," _" :" linkage disequilibrium MAF" },{" #name" :" keyword" ," $" :{" id" :" kw0145" }," $$" :[{" #name" :" text" ," _" :" minor allele frequency LC" },{" #name" :" keyword" ," $" :{" id" :" kw0155" }," $$" :[{" #name" :" text" ," _" :" lung cancer HWE" },{" #name" :" keyword" ," $" :{" id" :" kw0165" }," $$" :[{" #name" :" text" ," _" :" Hardy-Weinberg equilibrium BER" },{" #name" :" keyword" ," $" :{" id" :" kw0175" }," $$" :[{" #name" :" text" ," _" :" base excision repair pathway NHEJ" },{" #name" :" keyword" ," $" :{" id" :" kw0185" }," $$" :[{" #name" :" text" ," _" :" non-homologous end joining |
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