Albert Rosenberger1, Rayjean J Hung2, David C Christiani3, Neil E Caporaso4, Geoffrey Liu2, Stig E Bojesen5,6,7, Loic Le Marchand8, Ch A Haiman9, Demetrios Albanes4, Melinda C Aldrich10, Adonina Tardon11, G Fernández-Tardón11, Gad Rennert12, John K Field13, B Kiemeney14, Philip Lazarus15, Aage Haugen16, Shanbeh Zienolddiny16, Stephen Lam17, Matthew B Schabath18, Angeline S Andrew19, Hans Brunnsstöm20, Gary E Goodman21, Jennifer A Doherty19,22,23, Chu Chen22, M Dawn Teare24, H-Erich Wichmann25,26,27, Judith Manz25,28, Angela Risch29,30,31, Thomas R Muley29,30, Mikael Johansson32, Paul Brennan33, Maria Teresa Landi4, Christopher I Amos34, Beate Pesch35, Georg Johnen35, Thomas Brüning35, Heike Bickeböller36, Maria Gomolka37. 1. Department of Genetic Epidemiology, University Medical Center, Georg August University Göttingen, Humboldtallee 32, 37073, Göttingen, Germany. arosenb@gwdg.de. 2. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto, Toronto, ON, Canada. 3. Department of Environmental Health, Harvard T.H. Chan School of Public Health and Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA. 4. Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, MD, USA. 5. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. 6. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 7. Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark. 8. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA. 9. Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA. 10. Division of Epidemiology, Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. 11. Faculty of Medicine, University of Oviedo and CIBERESP, Oviedo, Spain. 12. Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel. 13. Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 14. Departments of Health Evidence and Urology, Radboud University Medical Center, Nijmegen, The Netherlands. 15. Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA. 16. National Institute of Occupational Health, Oslo, Norway. 17. British Columbia Cancer Agency, Vancouver, BC, Canada. 18. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. 19. Department of Epidemiology, Geisel School of Medicine, Hanover, NH, USA. 20. Laboratory Medicine Region Skåne, Department of Clinical Sciences and Pathology, Lund University, Lund, Sweden. 21. Swedish Medical Group, Seattle, WA, USA. 22. Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 23. Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. 24. School of Health and Related Research, University of Sheffield, Sheffield, UK. 25. Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. 26. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany. 27. Institute of Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany. 28. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. 29. Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany. 30. Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany. 31. University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria. 32. Department of Radiation Sciences, Umeå University, Umeå, Sweden. 33. International Agency for Research on Cancer, World Health Organization, Lyon, France. 34. Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. 35. Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), Bochum, Germany. 36. Department of Genetic Epidemiology, University Medical Center, Georg August University Göttingen, Humboldtallee 32, 37073, Göttingen, Germany. 37. Unit Biological Radiation Effects, Biological Dosimetry, Department of Radiation Protection and Health, Federal Office for Radiation Protection, BfS, Neuherberg, Germany.
Abstract
PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.
PURPOSE: Radon is a risk factor for lung cancer and uraniumminers are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uraniumminers collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uraniumminers were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uraniumminers. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.
Entities:
Keywords:
DNA repair; GWAS; Gene–environment interaction; Occupational exposure; Radon progeny
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