Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies

Yafang Li; Xiangjun Xiao; Jianrong Li; Younghun Han; Chao Cheng; Gail F. Fernandes; Shannon E. Slewitzke; Susan M. Rosenberg; Meng Zhu; Jinyoung Byun; Yohan Bosse; 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; Christopher I. Amos

doi:10.1158/1055-9965.EPI-23-0613

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies

Yafang Li
, Xiangjun Xiao
, Jianrong Li
, Younghun Han
, Chao Cheng
, Gail F. Fernandes
, Shannon E. Slewitzke
, Susan M. Rosenberg
, Meng Zhu
, Jinyoung Byun
, Yohan Bosse
, 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, Christopher I. Amos

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	389-399
Number of pages	11
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	33
Issue number	3
DOIs	https://doi.org/10.1158/1055-9965.EPI-23-0613
State	Published - Mar 1 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors; Published by the American Association for Cancer Research.

Funding

The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from dbGaP accession number phs000424.v7. p2. Thanks to Kathryn Edwards and Zachary Xiao for proofreading the article. The research in this study is supported by the NCI of the NIH under award numbers U19CA203654, U01CA243483, R21CA235464; by Cancer Prevention Research Institute of Texas (CPRIT) under award numbers RR170048, RR160097T, RR180061; by the Department of Health and Human Services contracts under award numbers HHSN26820100007C, HHSN268201700012C, 75N92020C00001; by NCI of the NIH under award number X01HG007491 under contract number HHSN268201200008I. The CARET study is funded by the NCI of the NIH under award numbers U01CA063673, UM1CA167462, and U01CA167462; the Harvard Lung Cancer Study is funded by the NCI of the NIH under award number U01CA209414; the Asian validation study is funded by the National Natural Science Foundation of China under award number 81820108028; the Liverpool Lung Project is supported by MPAD Roy Castle Lung Foundation (UK); the EAGLE study is supported by the intramural program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute of the NIH; the ReSoLuCENT study is funded by the Weston Park Hospital Cancer Charity. Acknowledgment to the George IsAFRc Family Fund for Cancer Research for grant support. J.E. Bailey-Wilson was supported by the Intramural Research Program of the National Human Genome Research Institute at NIH. J. Xia was supported by the National Institute of Environmental Health Sciences of the NIH under award number KK99ES033259, the Nebraska Health Care Funding Act LB692, and Cancer and Smoking Disease Research Program LB595. S.M. Rosenberg was supported by NCI of the NIH under award number R01CA250905 and by the National Institute on Aging of NIH under award number DP1AG072751. This project was also supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support under award number RP180672, the NIH under award number P30CA125123 and S10RR024574, and the assistance of Joel M Sederstrom. C.I Amos and C. Cheng are Research Scholars at the Cancer Prevention Institute of Texas. S.M. Rosenberg reports part of this work was funded by U.S. NIH grant R01-CA250905. A. Risch reports grants from Deutsche Krebshilfe and NIH during the conduct of the study. S.M. Arnold reports other support from Merck Sharp & Dohme, AstraZeneca Pharma, Ellipses Pharma Limited, AbbVie Incorporated, LabCorp, Exelixis, Incyte Corp, Eli Lilly, Beigene, and Kinnate Biopharma Inc outside the submitted work. M.P.A. Davies reports grants from Roy Castle Lung Cancer Foundation during the conduct of the study. L. Le Marchand reports grants from NCI during the conduct of the study. M.C. Aldrich reports grants from NIH/NCI during the conduct of the study; personal fees from Guardant Health outside the submitted work. A.G. Schwartz reports grants from NIH during the conduct of the study. K.S. Purrington reports grants from NCI during the conduct of the study. S.M. Pinney reports grants from NCI and National Institute of Environmental Health Sciences during the conduct of the study. C.I. Amos reports grants from NCI during the conduct of the study. No disclosures were reported by the other authors. The CARET study is funded by the NCI of the NIH under award numbers U01CA063673, UM1CA167462, and U01CA167462; the Harvard Lung Cancer Study is funded by the NCI of the NIH under award number U01CA209414; the Asian validation study is funded by the National Natural Science Foundation of China under award number 81820108028; the Liverpool Lung Project is supported by MPAD Roy Castle Lung Foundation (UK); the EAGLE study is supported by the intramural program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute of the NIH; the ReSoLuCENT study is funded by the Weston Park Hospital Cancer Charity. Acknowledgment to the George IsAFRc Family Fund for Cancer Research for grant support. J.E. Bailey-Wilson was supported by the Intramural Research Program of the National Human Genome Research Institute at NIH. J. Xia was supported by the National Institute of Environmental Health Sciences of the NIH under award number KK99ES033259, the Nebraska Health Care Funding Act LB692, and Cancer and Smoking Disease Research Program LB595. S.M. Rosenberg was supported by NCI of the NIH under award number R01CA250905 and by the National Institute on Aging of NIH under award number DP1AG072751. This project was also supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support under award number RP180672, the NIH under award number P30CA125123 and S10RR024574, and the assistance of Joel M Sederstrom. C.I Amos and C. Cheng are Research Scholars at the Cancer Prevention Institute of Texas. The research in this study is supported by the NCI of the NIH under award numbers U19CA203654, U01CA243483, R21CA235464; by Cancer Prevention Research Institute of Texas (CPRIT) under award numbers RR170048, RR160097T, RR180061; by the Department of Health and Human Services contracts under award numbers HHSN26820100007C, HHSN268201700012C, 75N92020C00001; by NCI of the NIH under award number X01HG007491 under contract number HHSN268201200008I.

Funders	Funder number
National Institute of Mental Health
National Human Genome Research Institute
Weston Park Hospital Cancer Charity
National Childhood Cancer Registry – National Cancer Institute
Author National Institute on Drug Abuse DA031791 Mark J Ferris National Institute on Drug Abuse DA006634 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA026117 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA028162 Elizabeth G Pitts National Institute of General Medical Sciences GM102773 Elizabeth G Pitts Peter McManus Charitable Trust Mark J Ferris National Institute on Drug Abuse
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute Division of Cancer Epidemiology and Genetics
Deutsche Krebshilfe
Roy Castle Lung Cancer Foundation
MPAD Roy Castle Lung Foundation
Cancer Prevention and Research Institute of Texas	RR170048, P30CA125123, S10RR024574, RR180061, RR160097T
National Institutes of Health/National Institute of Environmental Health Sciences	LB692, R01CA250905, LB595, KK99ES033259
National Institute on Aging	P30CA125123, S10RR024574, DP1AG072751, RP180672
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	phs000424.v7, U19CA203654, U01CA243483, R21CA235464
U.S. Department of Health and Human Services	U01CA063673, U01CA167462, U01CA209414, HHSN268201700012C, HHSN268201200008I, 75N92020C00001, UM1CA167462, HHSN26820100007C, X01HG007491
National Institutes of Health (NIH)	U01CA063673, U01CA209414, UM1CA167462
U.S. NIH	R01-CA250905
National Natural Science Foundation of China (NSFC)	81820108028

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Epidemiology
Oncology

Access to Document

10.1158/1055-9965.EPI-23-0613

Cite this

Li, Y., Xiao, X., Li, J., Han, Y., Cheng, C., Fernandes, G. F., Slewitzke, S. E., Rosenberg, S. M., Zhu, M., Byun, J., Bosse, Y., McKay, J. D., Albanes, D., Lam, S., Tardon, A., Chen, C., Bojesen, S. E., Landi, M. T., Johansson, M., ... Amos, C. I. (2024). Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies. Cancer Epidemiology Biomarkers and Prevention, 33(3), 389-399. https://doi.org/10.1158/1055-9965.EPI-23-0613

@article{7a8a364320f24fb9bc799e906f6ff793,

title = "Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies",

abstract = "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.",

author = "Yafang Li and Xiangjun Xiao and Jianrong Li and Younghun Han and Chao Cheng and Fernandes, \{Gail F.\} and Slewitzke, \{Shannon E.\} and Rosenberg, \{Susan M.\} and Meng Zhu and Jinyoung Byun and Yohan Bosse and McKay, \{James D.\} and Demetrios Albanes and Stephen Lam and Adonina Tardon and Chu Chen and Bojesen, \{Stig E.\} and Landi, \{Maria T.\} and Mattias Johansson and Angela Risch and Heike Bickeb{\"o}ller and Wichmann, \{H. Erich\} and Christiani, \{David C.\} and Gad Rennert and Arnold, \{Susanne M.\} and Goodman, \{Gary E.\} and Field, \{John K.\} and Davies, \{Michael P.A.\} and Sanjay Shete and \{Le Marchand\}, Lo{\"i}c and Geoffrey Liu and Hung, \{Rayjean J.\} and Andrew, \{Angeline S.\} and Kiemeney, \{Lambertus A.\} and Ryan Sun and Shanbeh Zienolddiny and Kjell Grankvist and Mikael Johansson and Caporaso, \{Neil E.\} and Angela Cox and Hong, \{Yun Chul\} and Philip Lazarus and Schabath, \{Matthew B.\} and Aldrich, \{Melinda C.\} and Schwartz, \{Ann G.\} and Ivan Gorlov and Purrington, \{Kristen S.\} and Ping Yang and Yanhong Liu and Bailey-Wilson, \{Joan E.\} and Pinney, \{Susan M.\} and Diptasri Mandal and Willey, \{James C.\} and Colette Gaba and Paul Brennan and Jun Xia and Hongbing Shen and Amos, \{Christopher I.\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors; Published by the American Association for Cancer Research.",

year = "2024",

month = mar,

day = "1",

doi = "10.1158/1055-9965.EPI-23-0613",

language = "English",

volume = "33",

pages = "389--399",

number = "3",

}

Li, Y, Xiao, X, Li, J, Han, Y, Cheng, C, Fernandes, GF, Slewitzke, SE, Rosenberg, SM, Zhu, M, Byun, J, Bosse, Y, McKay, JD, Albanes, D, Lam, S, Tardon, A, Chen, C, Bojesen, SE, Landi, MT, Johansson, M, Risch, A, Bickeböller, H, Wichmann, HE, Christiani, DC, Rennert, G, Arnold, SM, Goodman, GE, Field, JK, Davies, MPA, Shete, S, Le Marchand, L, Liu, G, Hung, RJ, Andrew, AS, Kiemeney, LA, Sun, R, Zienolddiny, S, Grankvist, K, Johansson, M, Caporaso, NE, Cox, A, Hong, YC, Lazarus, P, Schabath, MB, Aldrich, MC, Schwartz, AG, Gorlov, I, Purrington, KS, Yang, P, Liu, Y, Bailey-Wilson, JE, Pinney, SM, Mandal, D, Willey, JC, Gaba, C, Brennan, P, Xia, J, Shen, H & Amos, CI 2024, 'Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies', Cancer Epidemiology Biomarkers and Prevention, vol. 33, no. 3, pp. 389-399. https://doi.org/10.1158/1055-9965.EPI-23-0613

TY - JOUR

T1 - Lung Cancer in Ever- and Never-Smokers

T2 - Findings from Multi-Population GWAS Studies

AU - Li, Yafang

AU - Xiao, Xiangjun

AU - Li, Jianrong

AU - Han, Younghun

AU - Cheng, Chao

AU - Fernandes, Gail F.

AU - Slewitzke, Shannon E.

AU - Rosenberg, Susan M.

AU - Zhu, Meng

AU - Byun, Jinyoung

AU - Bosse, Yohan

AU - McKay, James D.

AU - Albanes, Demetrios

AU - Lam, Stephen

AU - Tardon, Adonina

AU - Chen, Chu

AU - Bojesen, Stig E.

AU - Landi, Maria T.

AU - Johansson, Mattias

AU - Risch, Angela

AU - Bickeböller, Heike

AU - Wichmann, H. Erich

AU - Christiani, David C.

AU - Rennert, Gad

AU - Arnold, Susanne M.

AU - Goodman, Gary E.

AU - Field, John K.

AU - Davies, Michael P.A.

AU - Shete, Sanjay

AU - Le Marchand, Loïc

AU - Liu, Geoffrey

AU - Hung, Rayjean J.

AU - Andrew, Angeline S.

AU - Kiemeney, Lambertus A.

AU - Sun, Ryan

AU - Zienolddiny, Shanbeh

AU - Grankvist, Kjell

AU - Johansson, Mikael

AU - Caporaso, Neil E.

AU - Cox, Angela

AU - Hong, Yun Chul

AU - Lazarus, Philip

AU - Schabath, Matthew B.

AU - Aldrich, Melinda C.

AU - Schwartz, Ann G.

AU - Gorlov, Ivan

AU - Purrington, Kristen S.

AU - Yang, Ping

AU - Liu, Yanhong

AU - Bailey-Wilson, Joan E.

AU - Pinney, Susan M.

AU - Mandal, Diptasri

AU - Willey, James C.

AU - Gaba, Colette

AU - Brennan, Paul

AU - Xia, Jun

AU - Shen, Hongbing

AU - Amos, Christopher I.

PY - 2024/3/1

Y1 - 2024/3/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85186745004

UR - https://www.scopus.com/pages/publications/85186745004#tab=citedBy

U2 - 10.1158/1055-9965.EPI-23-0613

DO - 10.1158/1055-9965.EPI-23-0613

M3 - Article

C2 - 38180474

AN - SCOPUS:85186745004

SN - 1055-9965

VL - 33

SP - 389

EP - 399

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 3

ER -

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this