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.

• Keywords
• Hypoxia-inducible factor, Integrated analysis, Lung adenocarcinoma, Network analysis, Non-small cell lung cancer,
• MeSH
• Adenocarcinoma of Lung MeSH
• Adenocarcinoma genetics   pathology   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Association Studies MeSH
• Polymorphism, Single Nucleotide MeSH
• Middle Aged MeSH
• Humans MeSH
• DNA Methylation genetics   MeSH
• Lung Neoplasms genetics   pathology   MeSH
• Carcinoma, Non-Small-Cell Lung genetics   pathology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Aged MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• endothelial PAS domain-containing protein 1 MeSH Browser
• Hypoxia-Inducible Factor 1, alpha Subunit MeSH
• HIF1A protein, human MeSH Browser
• Basic Helix-Loop-Helix Transcription Factors MeSH