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

Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer.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 nove...

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Main Authors: Li, Yafang (Author) , Xiao, Xiangjun (Author) , Li, Jianrong (Author) , Han, Younghun (Author) , Cheng, Chao (Author) , Fernandes, Gail F. (Author) , Slewitzke, Shannon E. (Author) , Rosenberg, Susan M. (Author) , Zhu, Meng (Author) , Byun, Jinyoung (Author) , Bossé, Yohan (Author) , McKay, James D. (Author) , Albanes, Demetrios (Author) , Lam, Stephen (Author) , Tardon, Adonina (Author) , Chen, Chu (Author) , Bojesen, Stig E. (Author) , Landi, Maria T. (Author) , Johansson, Mattias (Author) , Risch, Angela (Author) , Bickeböller, Heike (Author) , Wichmann, H-Erich (Author) , Christiani, David C. (Author) , Rennert, Gad (Author) , Arnold, Susanne M. (Author) , Goodman, Gary E. (Author) , Field, John K. (Author) , Davies, Michael P.A. (Author) , Shete, Sanjay (Author) , Marchand, Loïc Le (Author) , Liu, Geoffrey (Author) , Hung, Rayjean J. (Author) , Andrew, Angeline S. (Author) , Kiemeney, Lambertus A. (Author) , Sun, Ryan (Author) , Zienolddiny, Shanbeh (Author) , Grankvist, Kjell (Author) , Johansson, Mikael (Author) , Caporaso, Neil E. (Author) , Cox, Angela (Author) , Hong, Yun-Chul (Author) , Lazarus, Philip (Author) , Schabath, Matthew B. (Author) , Aldrich, Melinda C. (Author) , Schwartz, Ann G. (Author) , Gorlov, Ivan (Author) , Purrington, Kristen S. (Author) , Yang, Ping (Author) , Liu, Yanhong (Author) , Bailey-Wilson, Joan E. (Author) , Pinney, Susan M. (Author) , Mandal, Diptasri (Author) , Willey, James C. (Author) , Gaba, Colette (Author) , Brennan, Paul (Author) , Xia, Jun (Author) , Shen, Hongbing (Author) , Amos, Christopher I. (Author)
Format: Article (Journal)
Language:English
Published: 1 March 2024
In: Cancer epidemiology, biomarkers & prevention
Year: 2024, Volume: 33, Issue: 3, Pages: 389-399
ISSN:1538-7755
DOI:10.1158/1055-9965.EPI-23-0613
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/1055-9965.EPI-23-0613
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Author Notes:Yafang Li, Xiangjun Xiao, Jianrong Li, Younghun Han, Chao Cheng, Gail F. Fernandes, Shannon E. Slewitzke, Susan M. Rosenberg, Meng Zhu, Jinyoung Byun, Yohan Bossé, James D. McKay, Demetrios Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Maria T. Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, David C. Christiani, Gad Rennert, Susanne M. Arnold, Gary E. Goodman, John K. Field, Michael P.A. Davies, Sanjay Shete, Loïc Le Marchand, Geoffrey Liu, Rayjean J. Hung, Angeline S. Andrew, Lambertus A. Kiemeney, Ryan Sun, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E. Caporaso, Angela Cox, Yun-Chul Hong, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Ann G. Schwartz, Ivan Gorlov, Kristen S. Purrington, Ping Yang, Yanhong Liu, Joan E. Bailey-Wilson, Susan M. Pinney, Diptasri Mandal, James C. Willey, Colette Gaba, Paul Brennan, Jun Xia, Hongbing Shen, and Christopher I. Amos

MARC

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520 |a Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer.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.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.We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies.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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