TY - JOUR
T1 - Genetic modifiers of radon-induced lung cancer risk
T2 - a genome-wide interaction study in former uranium miners
AU - Rosenberger, Albert
AU - Hung, Rayjean J.
AU - Christiani, David C.
AU - Caporaso, Neil E.
AU - Liu, Geoffrey
AU - Bojesen, Stig E.
AU - Le Marchand, Loic
AU - Haiman, Ch A.
AU - Albanes, Demetrios
AU - Aldrich, Melinda C.
AU - Tardon, Adonina
AU - Fernández-Tardón, G.
AU - Rennert, Gad
AU - Field, John K.
AU - Kiemeney, B.
AU - Lazarus, Philip
AU - Haugen, Aage
AU - Zienolddiny, Shanbeh
AU - Lam, Stephen
AU - Schabath, Matthew B.
AU - Andrew, Angeline S.
AU - Brunnsstöm, Hans
AU - Goodman, Gary E.
AU - Doherty, Jennifer A.
AU - Chen, Chu
AU - Teare, M. Dawn
AU - Wichmann, H. Erich
AU - Manz, Judith
AU - Risch, Angela
AU - Muley, Thomas R.
AU - Johansson, Mikael
AU - Brennan, Paul
AU - Landi, Maria Teresa
AU - Amos, Christopher I.
AU - Pesch, Beate
AU - Johnen, Georg
AU - Brüning, Thomas
AU - Bickeböller, Heike
AU - Gomolka, Maria
PY - 2018
Y1 - 2018
N2 -
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.
AB -
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.
KW - DNA repair
KW - Gene–environment interaction
KW - GWAS
KW - Occupational exposure
KW - Radon progeny
U2 - 10.1007/s00420-018-1334-3
DO - 10.1007/s00420-018-1334-3
M3 - Journal article
C2 - 29971594
AN - SCOPUS:85049594611
VL - 91
SP - 937
EP - 950
JO - International Archives of Occupational and Environmental Health
JF - International Archives of Occupational and Environmental Health
SN - 0340-0131
IS - 8
ER -