Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium revealed a SNP (rs12614710) in EPAS1 associated with NSCLC that reached genome-wide significance (OR = 1.50; 95% CI: 1.31-1.72; p = 7.75 × 10-9). Using imputed data, we found that this SNP remained significant in the entire TRICL-ILCCO consortium (p = .03). Additional functional studies are warranted to better understand interrelationships among genetic polymorphisms, DNA methylation status, and EPAS1 expression.

Biomedical Data Science Geisel School of Medicine at Dartmouth Hanover NH USA

Center for Inherited Disease Research Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore MD USA

Clinic of Pulmonology Clinical Center of Serbia Belgrade Serbia

Department of Biostatistics Harvard T H Chan School of Public Health Boston MA USA

Department of Biostatistics School of Public Health University of Washington Seattle WA USA

Department of Cancer Epidemiology and Prevention M Sklodowska Curie Institute Oncology Center Warsaw Poland

Department of Environmental Health Harvard T H Chan School of Public Health Boston MA USA

Department of Environmental Health Harvard T H Chan School of Public Health Boston MA USA; Department of Epidemiology Department of Biostatistics School of Public Health Nanjing Medical University Nanjing China

Department of Epidemiology and Public Health University of Ostrava University of Olomouc Olomouc Czech Republic

Department of Epidemiology Department of Biostatistics School of Public Health Nanjing Medical University Nanjing China

Genetic Cancer Susceptibility group International Agency for Research on Cancer World Health Organization Lyon France

Institute of Translational Medicine University of Liverpool Liverpool United Kingdom

Lunenfeld Tanenbaum Research Institute Sinai Health System University of Toronto Toronto Canada

Nofer Institute of Occupational Medicine Department of Environmental Epidemiology Lodz Poland

Princess Margaret Cancer Centre Toronto Canada

Russian N N Blokhin Cancer Research Centre Moscow Russian Federation

Thoracic Surgery Division Marius Nasta National Institute of Pneumology Bucharest Romania

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Rare deleterious germline variants and risk of lung cancer