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Publications

Journal Article Ahead of print

PubMed: 42895475 DOI: 10.1158/1055-9965.EPI-26-0120

Large-scale association study identifies lung cancer susceptibility copy number variants and their potential functional role in genetic instability.

Cancer Epidemiol Biomarkers Prev

Authors: Feifei Xiao, Fei Qin, Xizhi Luo, Shannon E Slewitzke, Gail F Fernandes, Mattias Johansson, Xiangjun Xiao, David Zaridze, Stig E Bojesen, Sanjay Shete, Demetrius Albanes, Melinda C Aldrich, Adonina Tardon, Guillermo Fernandez-Tardon, Loïc Le Marchand, Gad Rennert, Heike Bickeböller, H-Erich Wichmann, Angela Risch, Thomas Muley, Albert Rosenberger, John K Field, Michael P A Davies, Penella J Woll, Lambertus A Kiemeney, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Mikael Johansson, Kjell Grankvist, Matthew B Schabath, Angeline S Andrew, Philip Lazarus, Susanne M Arnold, Dakai Zhu, Hermann Brenner, Marian L Neuhouser, Rayjean J Hung, David C Christiani, James D McKay, Guoshuai Cai, Jun Xia, Christopher I Amos

Affiliations

  • University of Florida Gainesville, FL United States.
  • National Cancer Institute Rockville United States.
  • AbbVie Inc. North Chicago, Il United States.
  • Baylor College of Medicine Houston United States.
  • Centre international de recherche sur le cancer Lyon France.
  • UNM Comprehensive Cancer Center United States.
  • Russian Cancer Research Center NN Blokhin Moscow Russia.
  • Copenhagen University Hospital Herlev Denmark.
  • The University of Texas MD Anderson Cancer Center Houston, TX United States.
  • National Cancer Institute Bethesda, MD United States.
  • Vanderbilt University Medical Center Nashville United States.
  • Instituto de Investigación Sanitaria del Principado de Asturias Avilés Spain.
  • University of Hawaii Cancer Center Honolulu, Hawaii United States.
  • Technion - Israel Institute of Technology Haifa Israel.
  • Universitätsmedizin Göttingen Göttingen Germany.
  • Helmholtz Zentrum München Germany.
  • University of Salzburg Salzburg Austria.
  • University Hospital Heidelberg Heidelberg Germany.
  • University of Liverpool Liverpool UK United Kingdom.
  • University of Sheffield SHEFFIELD United Kingdom.
  • Radboud University Medical Centre Nijmegen Netherlands.
  • National Institute of Occupational Health Oslo Norway.
  • National Institute of Occupational Health Oslo, Oslo Norway.
  • University of British Columbia Vancouver, British Columbia Canada.
  • Umeå University Umea Sweden.
  • H. Lee Moffitt Cancer Center & Research Institute Tampa, FL United States.
  • Geisel School of Medicine at Dartmouth Lebanon, NH United States.
  • University at Buffalo, State University of New York United States.
  • University of Kentucky Lexington, KY United States.
  • German Cancer Research Center Heidelberg Germany.
  • Fred Hutch Cancer Center Seattle, WA United States.
  • Sinai Health System Toronto, Ontario Canada.
  • Harvard School of Public Health Boston, MA United States.
  • Centre international de recherche sur le cancer 69372 Lyon CEDEX 08 France.
  • University of Florida United States.
  • Texas A&M Health Science Center Houston, TX United States.
  • UNM Comprehensive Cancer Center Albuquerque, NM United States.

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.

MeSH

Genes, Lung, Neoplasms, Lung Neoplasms, Genomic Instability, Polymorphism, Single Nucleotide