Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma.
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Gogarten, Stephanie M
Field, John K
McKay, James D
Laurie, Cathy C
Doheny, Kimberly F
Pugh, Elizabeth K
Marosy, Beth A
Hetrick, Kurt N
Hung, Rayjean J
Amos, Christopher I
Christiani, David C
AffiliationNofer Institute of Occupational Medicine
MetadataShow full item record
AbstractRecent 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.
CitationEBioMedicine 2018, 32:93-101
SponsorsThis work was supported by the National Institutes of Health (NIH CA092824, CA090578, CA074386, and CA209414). Funding source for KFD, EWP, KNH, BAM (affiliation 7) is NIH contract HHSN268201200008I. The Toronto MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The data harmonization of the epidemiological variables across the studies is supported by National Institute of Health (U19-CA148127) and Lunenfeld-Tanenbaum Research Institute, Sinai Health System.
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