Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners
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.
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.
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.
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.
KeywordsGWAS Radon progeny Occupational exposure Gene–environment interaction DNA repair
This investigation, and the data sources used, were funded by following bodies: Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (Bundesministerium für Umwelt, Naturschutz und Reaktorsicherheit, BMU) (3608S04532 to G. Johnen and B. Pesch for sample collection of the German Uranium Miners Bio- and Databank (GUMB), 3614S10013, 3614S10014, 3615S32253 to H. Bickeböller for planning, genotyping, quality control and analysis of this project). National Institutes of Health (U19-CA148127, CA148127S1, 1U19CA148127-02 to Transdisciplinary Research for Cancer in Lung). Cancer Care Ontario Research (to R. J. Hung for ILCCO data harmonization). FIS-FEDER/Spain (FIS-01/310, FIS-PI03- 0365, FIS-07-BI060604 for the CAPUA study). FICYT/Asturias (FICYT PB02-67 and FICYT IB09-133 for the CAPUA study). National Institute of Health/National Cancer Institute (UM1 CA167462 to G. E. Goodman for the CARET study). National Institute of Health R01 (CA111703 to C. Chen, 5R01 CA151989-01A1 to J. A. Doherty, both for the CARET study). Roy Castle Lung Cancer Foundation (for the Liverpool Lung project). National Cancer Institute (CA092824, CA090578, CA074386; for the Harvard Lung Cancer Study). Canadian Cancer Society Research Institute (020214 for the MSH-PMH study). Ontario Institute of Cancer and Cancer Care Ontario Chair Award (to R. J. Hung and G. Liu for the MSH-PMH study). Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation (for the MSH-PMH study). Norwegian Cancer Society/Norwegian Research Council (for the Norway study). James and Esther King Biomedical Research Program (09KN-15, for the TLC study). National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997, for the TLC study). Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute (P30-CA76292, for the TLC study). Vanderbilt University Medical Center’s BioVU (1S10RR025141-01, for the Vanderbilt Lung Cancer Study). National Center for Advancing Translational Sciences (UL1TR000445 for the Vanderbilt Lung Cancer Study). National Cancer Institute (K07CA172294 to Aldrich for the Vanderbilt Lung Cancer Study). National Genome Research Institute (U01HG004798, to Crawford for the Vanderbilt Lung Cancer Study). Chief Physician Johan Boserup and Lise Boserup Fund/Danish Medical Research Council and Herlev Hospital (for the Copenhagen General Population Study). National Center for Research Resources (P20RR018787 for the NELCS study). Department of Defense/Congressionally Directed Medical Research Program, US Army Medical Research and Materiel Command Program 10153006 (W81XWH-11-1-0781 for NELCS study within the Kentucky Lung Cancer Research Initiative). International Agency for Research on Cancer (for coordination the IARC L2 study). National Institutes of Health (R01-DE12206, P01-CA68384, R01-DE13158 for the Tampa Lung Cancer Study). Terry Fox Research Institute and the Canadian Partnership Against Cancer (for the Pan-Canadian Early Detection of Lung Cancer Study).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The sampling of blood from the Wismut miners was approved by the Bavarian Medical Association (Bayerische Landesärztekammer) #08082 and the German Federal Commissioner for data protection and freedom of information. This research received approval from the Dartmouth Committee for Protection of Human Subjects on 7/30/2014 with id STUDY00023602.
Informed consent was obtained from all individual participants included in the study.
- Chen HJ et al (2015a) Contribution of genotype of DNA double-strand break repair gene XRCC3, gender, and smoking behavior to lung cancer risk in Taiwan. Anticancer Res 35(7):3893–3899Google Scholar
- Guo Y, An L, Ng HM, Sy SM, Huen MS (2017) An E2-guided E3 screen identifies the RNF17–UBE2U pair as regulator of the radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties (RIDDLE) syndrome protein RNF168. J Biol Chem 292(3):967–978. https://doi.org/10.1074/jbc.M116.758854 CrossRefGoogle Scholar
- Kreuzer M, Grosche B, Schnelzer M, Tschense A, Dufey F, Walsh L (2010a) Radon and risk of death from cancer and cardiovascular diseases in the German uranium miners cohort study: follow-up 1946–2003. Radiat Environ Biophys 49(2):177–185. https://doi.org/10.1007/s00411-009-0249-5 CrossRefGoogle Scholar
- National Research Council (1999) Health effects of exposure to radon. BEIR VI, Washington (DC)Google Scholar
- Pesch B, Johnen G, Lehnert M (2015) Aufbau einer Bioproben-Bank von ehemaligen Beschäftigten der SAG/SDAG Wismut—Pilotstudie. Ressortforschungsberichte zur kerntechnischen Sicherheit und zum Strahlenschutz. BfS-Bundesamt für Strahlenschutz. https://doris.bfs.de/jspui/handle/urn:nbn:de:0221-2015102213745. Accessed 29 Jun 2017
- Romero-Laorden N, Castro E (2017) Inherited mutations in DNA repair genes and cancer risk. Curr Probl Cancer 41(4):251–264. https://doi.org/10.1016/j.currproblcancer.2017.02.009 CrossRefGoogle Scholar
- Ruano-Ravina A, Pereyra MF, Castro MT, Perez-Rios M, Abal-Arca J, Barros-Dios JM (2014) Genetic susceptibility, residential radon, and lung cancer in a radon prone area. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 9(8):1073–1080. https://doi.org/10.1097/JTO.0000000000000205 CrossRefGoogle Scholar
- Sethi TK, El-Ghamry MN, Kloecker GH (2012) Radon and lung cancer. Clin Adv Hematol Oncol 10(3):157–164Google Scholar
- Stenzel SL, Ahn J, Boonstra PS, Gruber SB, Mukherjee B (2015) The impact of exposure-biased sampling designs on detection of gene–environment interactions in case–control studies with potential exposure misclassification. Eur J Epidemiol 30(5):413–423. https://doi.org/10.1007/s10654-014-9908-1 CrossRefGoogle Scholar
- Yngveson A, Williams C, Hjerpe A, Lundeberg J, Soderkvist P, Pershagen G (1999) p53 Mutations in lung cancer associated with residential radon exposure. Cancer Epidemiol Biomark Prev 8(5):433–438Google Scholar