Large-scale association study identifies lung cancer susceptibility copy number variants and their potential functional role in genetic instability
Abstract
BACKGROUND: Genome-wide association studies (GWAS) have identified numerous lung cancer susceptibility loci based on single nucleotide polymorphisms (SNPs), yet a substantial proportion of heritability remains unexplained. We therefore evaluated germline copy number variants (CNVs) as an underexplored source of genetic susceptibility and potential contributors to genomic instability in lung cancer. METHODS: We conducted a genome-wide analysis of germline CNVs using 19,342 cases and 15,917 controls from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, with replication in two independent cohorts. High-confidence CNVs were identified by integrating two CNV callers including PennCNV and modSaRa2. Association analyses were performed using both gene-based and CNV region-based approaches. Polygenic risk scores (PRS) were constructed from top loci, and functional validation was conducted using siRNA-mediated knockdown in lung fibroblast cells. RESULTS: We identified CNVs in four genomic regions (1p36.22, 2q31.2, 6p21.32, and 19q13.32) significantly or suggestively associated with lung cancer risk. Two loci (1p36.22 and 2q31.2) were consistently supported across both analytical strategies. A CNV-based PRS constructed from four key genes (CLCN6, NFE2L2, OPA3, and PSMB8) was significantly associated with lung cancer risk and replicated across independent datasets. Functional assays demonstrated that knockdown of NFE2L2 and OPA3 increased endogenous DNA damage, supporting a role in genomic stability. CONCLUSIONS: Germline CNVs contribute to lung cancer susceptibility and may influence carcinogenesis through mechanisms related to genomic instability. IMPACT: These findings expand our knowledge of the genetic architecture of lung cancer and suggest that the cumulative burden of germline CNVs may contribute to lung cancer susceptibility.
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Authors: Feifei Xiao, Fei Qin, Xizhi Luo, Shannon E. Slewitzke, Gail F. Fernandes, Mattias Johansson, Xiangjun Xiao, Д Г Заридзе, Stig E. Bojesen, Sanjay Shete, Demetrios Albanes, Melinda C. Aldrich, Adonina Tardón, Guillermo Fernández‐Tardón, Loı̈c Le Marchand, Gad Rennert, Heike Bickeböller, H.‐Erich Wichmann, Angela Risch, Thomas Muley, Albert Rosenberger, John K. Field, Michael Davies, Penella J. Woll, Lambertus A.L.M. Kiemeney, Aage Haugen, Shan Zienolddiny, Stephen C. Lam, Mikael Johansson, Kjell Grankvist, Matthew B. Schabath, Angeline S. Andrew, Philip J. Lazarus, Susanne M. Arnold, Zhu Dakai, Hermann Brenner, Marian L Neuhouser, Rayjean J. Hung, David C. Christiani, James McKay, Guoshuai Cai, Jun Xia, Christopher Ian Amos
Institutions: University of Florida, Florida College, University of British Columbia, University of Sheffield, Harvard University, University at Buffalo, State University of New York, University of Liverpool, Universitätsmedizin Göttingen, Heidelberg University, University Hospital Heidelberg, The University of Texas MD Anderson Cancer Center, Radboud University Nijmegen, Dartmouth College, National Cancer Institute, German Cancer Research Center, National Cancer Institute, Instituto de Investigación Sanitaria del Principado de Asturias, University of Kentucky, AbbVie (United States), Sinai Health System, Moffitt Cancer Center, Russian Cancer Research Center NN Blokhin, University of Salzburg, Baylor College of Medicine, Radboud University Medical Center, Vanderbilt University Medical Center, Umeå University, Technion – Israel Institute of Technology, Herlev Hospital, Helmholtz Munich, Fred Hutch Cancer Center, Centre de Recherche en Cancérologie de Lyon, Centre international de recherche sur le cancer, Massachusetts Department of Public Health, Dartmouth Psychiatric Research Center, Pädagogische Hochschule Salzburg, National Institute of Occupational Health, Cancer Center of Hawaii, Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa, New Mexico Cancer Center, Texas A&M Health Science Center