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Li, Y.* ; Xiao, X.* ; Li, J.* ; Han, Y.* ; Cheng, C.* ; Fernandes, G.F.* ; Slewitzke, S.E.* ; Rosenberg, S.M.* ; Zhu, M.* ; Byun, J.* ; Bossé, Y.* ; McKay, J.D.* ; Albanes, D.* ; Lam, S.* ; Tardón, A.* ; Chen, C.* ; Bojesen, S.E.* ; Landi, M.T.* ; Johansson, M.* ; Risch, A.* ; Bickeböller, H.* ; Wichmann, H.-E. ; Christiani, D.C.* ; Rennert, G.* ; Arnold, S.M.* ; Goodman, G.E.* ; Field, J.K.* ; Davies, M.P.A.* ; Shete, S.* ; Le Marchand, L.* ; Liu, G.* ; Hung, R.J.* ; Andrew, A.S.* ; Kiemeney, L.A.* ; Sun, R.* ; Zienolddiny, S.* ; Grankvist, K.* ; Caporaso, N.E.* ; Cox, A.* ; Hong, Y.C.* ; Lazarus, P.* ; Schabath, M.B.* ; Aldrich, M.C.* ; Schwartz, A.G.* ; Gorlov, I.* ; Purrington, K.S.* ; Yang, P.* ; Liu, Y.* ; Bailey-Wilson, J.E.* ; Pinney, S.M.* ; Mandal, D.* ; Willey, J.C.* ; Gaba, C.* ; Brennan, P.* ; Xia, J.* ; Shen, H.* ; Amos, C.I.*

Lung cancer in ever- and never-smokers: Findings from multi-population GWAS studies.

Cancer Epidemiol. Biomarkers Prev. 33, 389-399 (2024)
Publ. Version/Full Text DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44, 823 ever-smokers and 20, 074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. Results: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 ͯ 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. Conclusions: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. Impact: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Genome-wide Association; Susceptibility Loci; Smoking; Metaanalysis; Sites; Risk
ISSN (print) / ISBN 1055-9965
e-ISSN 1538-7755
Journal Cancer Epidemiology, Biomarkers & Prevention
Quellenangaben Volume: 33, Issue: 3, Pages: 389-399 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Publishing Place 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Grants NINDS
NIMH
NIDA
NHLBI
NHGRI
NCI
Common Fund of the Office of the Director of the NIH
National Cancer Institute (NCI)