Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma

Abstract

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.

Detection and Independent Validation of Model-Based Quantitative Transcriptional Regulation Relationships Altered in Lung Cancers

“…Nucleus (6) and cytoplasm (8) are another two common sub-cellular locations for the proteins encoded by the genes with transcriptional regulations altered in lung cancers. EPAS1 is known to be a major transcriptional regulator associated with the diagnosis and prognosis of lung cancers (Wang et al, 2018;De Bastiani and Klamt, 2019;Zhang et al, 2019). This study detects that sixteen EPAS1-regulated genes demonstrated quantitatively altered transcriptional regulations in lung cancers.…”

Hypoxia‐sensitive LINC01436 is regulated by E2F6 and acts as an oncogene by targeting miR‐30a‐3p in non‐small cell lung cancer

“…However, the expression and clinical significance of EPAS1 in NSCLC tissues has not been definitively established. A recent multi‐omics analysis revealed that lung tumor tissues had low EPAS1 mRNA and protein expression compared with normal tissues (Wang et al ., ). In our present study, EPAS1 mRNA expression levels were not correlated with LINC01436 expression levels in lung tumor tissues and no difference was found for EPAS1 protein expression between lung tumor tissues and adjacent normal lung tissues (Fig.…”

Explaining the genetic causality for complex diseasesviadeep association kernel learning

“…The genotyping data of GWASs of gastric cancer and schizophrenia were deposited in the database of Genotypes and Phenotypes (dbGaP; phs000361 and phs000021, separately). The genotyping data of GWASs of colorectal cancer and lung cancer were derived from previous studies 46,47 .…”