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

Rosenberger, Albert; Hung, Rayjean J.; Christiani, David C.; Caporaso, Neil E.; Liu, Geoffrey; Bojesen, Stig E.; Le Marchand, Loic; Haiman, C. A.; Albanes, Demetrios and Aldrich, Melinda C., et al. (2018) In International Archives of Occupational and Environmental Health 91(8). p.937-950
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... (More)

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.

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publication status
published
subject
keywords
DNA repair, Gene–environment interaction, GWAS, Occupational exposure, Radon progeny
in
International Archives of Occupational and Environmental Health
volume
91
issue
8
pages
937 - 950
publisher
Springer
external identifiers
  • scopus:85049594611
ISSN
0340-0131
DOI
10.1007/s00420-018-1334-3
language
English
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yes
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f2a23017-f207-4870-a320-34e9558ef91a
date added to LUP
2018-07-23 10:41:11
date last changed
2019-01-14 17:35:07
@article{f2a23017-f207-4870-a320-34e9558ef91a,
  abstract     = {<p>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<sup>−6</sup>), 5q23.2 (p = 2.5 × 10<sup>−6</sup>), 1q21.3 (p = 3.2 × 10<sup>−6</sup>), 10p13 (p = 1.3 × 10<sup>−5</sup>) and 12p12.1 (p = 7.1 × 10<sup>−5</sup>). 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.</p>},
  author       = {Rosenberger, Albert and Hung, Rayjean J. and Christiani, David C. and Caporaso, Neil E. and Liu, Geoffrey and Bojesen, Stig E. and Le Marchand, Loic and Haiman, C. A. and Albanes, Demetrios and Aldrich, Melinda C. and Tardon, Adonina and Fernández-Tardón, G. and Rennert, Gad and Field, John K. and Kiemeney, B. and Lazarus, Philip and Haugen, Aage and Zienolddiny, Shanbeh and Lam, Stephen and Schabath, Matthew B. and Andrew, Angeline S. and Brunnsstöm, Hans and Goodman, Gary E. and Doherty, Jennifer A. and Chen, Chu and Teare, M. Dawn and Wichmann, H. E. and Manz, Judith and Risch, Angela and Muley, Thomas R. and Johansson, Mikael and Brennan, Paul and Landi, Maria Teresa and Amos, Christopher I. and Pesch, Beate and Johnen, Georg and Brüning, Thomas and Bickeböller, Heike and Gomolka, Maria},
  issn         = {0340-0131},
  keyword      = {DNA repair,Gene–environment interaction,GWAS,Occupational exposure,Radon progeny},
  language     = {eng},
  month        = {07},
  number       = {8},
  pages        = {937--950},
  publisher    = {Springer},
  series       = {International Archives of Occupational and Environmental Health},
  title        = {Genetic modifiers of radon-induced lung cancer risk : a genome-wide interaction study in former uranium miners},
  url          = {http://dx.doi.org/10.1007/s00420-018-1334-3},
  volume       = {91},
  year         = {2018},
}