Yafang Li, Baylor College of Medicine, Houston, TX
Xiangjun Xiao, Baylor College of Medicine, Houston, TX
Jianrong Li, Baylor College of Medicine, Houston, TX
Younghun Han, Baylor College of Medicine, Houston, TX
Chao Cheng, Baylor College of Medicine, Houston, TX
Gail F. Fernandes, Baylor College of Medicine, Houston, TX
Shannon E. Slewitzke, Baylor College of Medicine, Houston, TX
Susan M. Rosenberg, Baylor College of Medicine, Houston, TX
Meng Zhu, Nanjing Medical University, Nanjing, P.R. China
Jinyoung Byun, Baylor College of Medicine, Houston, TX
Yohan Bossé, Laval University, Quebec City, Canada
James D. McKay, World Health Organization, Lyon, France
Demetrios Albanes, NCI, NIH, Bethesda, MD
Stephan Lam, University of British Columbia, Vancouver, Canada
Adonina Tardon, University of Oviedo, ISPA and CIBERESP, Asturias, Spain
Chu Chen, Fred Hutchinson Cancer Center, Seattle, WA
Stig E. Bojesen, Copenhagen University Hospital, Copenhagen, Denmark
Maria T. Landi, NCI, NIH, Bethesda, MD
Mattias Johansson, World Health Organization, Lyon, France
Angela Risch, University Hospital Heidelberg, Germany
Heike Bickeböller, Georg-August-University Göttingen, Germany
H-Erich Wichmann, Helmholtz-Munich Institute of Epidemiology, Neuherberg, Germany
David C. Christiani, Harvard TH Chan School of Public Health, Boston, MA
Gad Rennert, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
Susanne M. Arnold, University of Kentucky, Markey Cancer Center, Lexington, KY
Gary E. Goodman, Swedish Cancer Institute, Seattle, WA
John K. Field, University of Liverpool, United Kingdom
Diptasri Mandal, LSU Health Sciences Center - New OrleansFollow
et al

Document Type


Publication Date


Publication Title

Cancer Epidemiology, Biomarkers & Prevention


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 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, inter-genic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5x10-8). 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 etiological insights into the complicated genetic architecture of this deadly cancer.

First Page


Last Page


PubMed ID