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Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners

  • Albert Rosenberger
  • Rayjean J. Hung
  • David C. Christiani
  • Neil E. Caporaso
  • Geoffrey Liu
  • Stig E. Bojesen
  • Loic Le Marchand
  • Ch. A. Haiman
  • Demetrios Albanes
  • Melinda C. Aldrich
  • Adonina Tardon
  • G. Fernández-Tardón
  • Gad Rennert
  • John K. Field
  • B. Kiemeney
  • Philip Lazarus
  • Aage Haugen
  • Shanbeh Zienolddiny
  • Stephen Lam
  • Matthew B. Schabath
  • Angeline S. Andrew
  • Hans Brunnsstöm
  • Gary E. Goodman
  • Jennifer A. Doherty
  • Chu Chen
  • M. Dawn Teare
  • H.-Erich Wichmann
  • Judith Manz
  • Angela Risch
  • Thomas R. Muley
  • Mikael Johansson
  • Paul Brennan
  • Maria Teresa Landi
  • Christopher I. Amos
  • Beate Pesch
  • Georg Johnen
  • Thomas Brüning
  • Heike Bickeböller
  • Maria Gomolka
Original Article

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.

Keywords

GWAS Radon progeny Occupational exposure Gene–environment interaction DNA repair 

Notes

Funding

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.

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.

Supplementary material

420_2018_1334_MOESM1_ESM.docx (926 kb)
Supplementary materials and methods, supplementary figures I–III, supplementary tables I–IV and further discussion of the gene–radon interaction at 10p13 and 12p12.1 can be found at Online Resource 1 (DOCX 926 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Albert Rosenberger
    • 1
  • Rayjean J. Hung
    • 2
  • David C. Christiani
    • 3
  • Neil E. Caporaso
    • 4
  • Geoffrey Liu
    • 2
  • Stig E. Bojesen
    • 5
    • 6
    • 7
  • Loic Le Marchand
    • 8
  • Ch. A. Haiman
    • 9
  • Demetrios Albanes
    • 4
  • Melinda C. Aldrich
    • 10
  • Adonina Tardon
    • 11
  • G. Fernández-Tardón
    • 11
  • Gad Rennert
    • 12
  • John K. Field
    • 13
  • B. Kiemeney
    • 14
  • Philip Lazarus
    • 15
  • Aage Haugen
    • 16
  • Shanbeh Zienolddiny
    • 16
  • Stephen Lam
    • 17
  • Matthew B. Schabath
    • 18
  • Angeline S. Andrew
    • 19
  • Hans Brunnsstöm
    • 20
  • Gary E. Goodman
    • 21
  • Jennifer A. Doherty
    • 19
    • 22
    • 23
  • Chu Chen
    • 22
  • M. Dawn Teare
    • 24
  • H.-Erich Wichmann
    • 25
    • 26
    • 27
  • Judith Manz
    • 25
    • 28
  • Angela Risch
    • 29
    • 30
    • 31
  • Thomas R. Muley
    • 29
    • 30
  • Mikael Johansson
    • 32
  • Paul Brennan
    • 33
  • Maria Teresa Landi
    • 4
  • Christopher I. Amos
    • 34
  • Beate Pesch
    • 35
  • Georg Johnen
    • 35
  • Thomas Brüning
    • 35
  • Heike Bickeböller
    • 1
  • Maria Gomolka
    • 36
  1. 1.Department of Genetic Epidemiology, University Medical CenterGeorg August University GöttingenGöttingenGermany
  2. 2.Lunenfeld-Tanenbaum Research Institute, Sinai Health SystemUniversity of TorontoTorontoCanada
  3. 3.Department of Environmental HealthHarvard T.H. Chan School of Public Health and Massachusetts General Hospital/Harvard Medical SchoolBostonUSA
  4. 4.Division of Cancer Epidemiology and Genetics, National Cancer InstituteUS National Institutes of HealthBethesdaUSA
  5. 5.Department of Clinical Biochemistry, Herlev and Gentofte HospitalCopenhagen University HospitalCopenhagenDenmark
  6. 6.Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  7. 7.Copenhagen General Population StudyHerlev and Gentofte HospitalCopenhagenDenmark
  8. 8.Epidemiology ProgramUniversity of Hawaii Cancer CenterHonoluluUSA
  9. 9.Department of Preventive Medicine, Keck School of MedicineUniversity of Southern California Norris Comprehensive Cancer CenterLos AngelesUSA
  10. 10.Division of Epidemiology, Department of Thoracic SurgeryVanderbilt University Medical CenterNashvilleUSA
  11. 11.Faculty of MedicineUniversity of Oviedo and CIBERESPOviedoSpain
  12. 12.Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of MedicineHaifaIsrael
  13. 13.Institute of Translational MedicineUniversity of LiverpoolLiverpoolUK
  14. 14.Departments of Health Evidence and UrologyRadboud University Medical CenterNijmegenThe Netherlands
  15. 15.Department of Pharmaceutical Sciences, College of PharmacyWashington State UniversitySpokaneUSA
  16. 16.National Institute of Occupational HealthOsloNorway
  17. 17.British Columbia Cancer AgencyVancouverCanada
  18. 18.Department of Cancer EpidemiologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  19. 19.Department of EpidemiologyGeisel School of MedicineHanoverUSA
  20. 20.Laboratory Medicine Region Skåne, Department of Clinical Sciences and PathologyLund UniversityLundSweden
  21. 21.Swedish Medical GroupSeattleUSA
  22. 22.Program in EpidemiologyFred Hutchinson Cancer Research CenterSeattleUSA
  23. 23.Department of Population Health Sciences, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  24. 24.School of Health and Related ResearchUniversity of SheffieldSheffieldUK
  25. 25.Institute of Epidemiology IIHelmholtz Zentrum München-German Research Center for Environmental HealthNeuherbergGermany
  26. 26.Institute of Medical Informatics, Biometry and EpidemiologyLudwig Maximilians UniversityMunichGermany
  27. 27.Institute of Medical Statistics and EpidemiologyTechnical University of MunichMunichGermany
  28. 28.Research Unit of Molecular EpidemiologyHelmholtz Zentrum München-German Research Center for Environmental HealthNeuherbergGermany
  29. 29.Thoraxklinik at University Hospital HeidelbergHeidelbergGermany
  30. 30.Translational Lung Research Center Heidelberg (TLRC-H)HeidelbergGermany
  31. 31.University of Salzburg and Cancer Cluster SalzburgSalzburgAustria
  32. 32.Department of Radiation SciencesUmeå UniversityUmeåSweden
  33. 33.International Agency for Research on CancerWorld Health OrganizationLyonFrance
  34. 34.Biomedical Data ScienceGeisel School of Medicine at DartmouthHanoverUSA
  35. 35.Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA)BochumGermany
  36. 36.Unit Biological Radiation Effects, Biological Dosimetry, Department of Radiation Protection and HealthFederal Office for Radiation Protection, BfSNeuherbergGermany

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