EGLN2 DNA methylation and expression interact with HIF1A to affect survival of early-stage NSCLC

Abstract

Hypoxia occurs frequently in human cancers and promotes stabilization and activation of hypoxia inducible factor (HIF). HIF-1α is specific for the hypoxia response, and its degradation mediated by three enzymes EGLN1, EGLN2 and EGLN3. Although EGLNs expression has been found to be related to prognosis of many cancers, few studies examined DNA methylation in EGLNs and its relationship to prognosis of early-stage non-small cell lung cancer (NSCLC). We analyzed EGLNs DNA methylation data from tumor tissue samples of 1,230 early-stage NSCLC patients, as well as gene expression data from The Cancer Genome Atlas. The sliding windows sequential forward feature selection method and weighted random forest were used to screen out the candidate CpG probes in lung adenocarcinomas (LUAD) and lung squamous cell carcinomas patients, respectively, in both discovery and validation phases. Then Cox regression was performed to evaluate the association between DNA methylation and overall survival. Among the 34 CpG probes in EGLNs, DNA methylation at cg25923056 EGLN2 was identified to be significantly associated with LUAD survival (HR = 1.02, 95% CI: 1.01-1.03, P = 9.90 × 10 -5 ), and correlated with EGLN2 expression (r = -0.36, P = 1.52 × 10 -11 ). Meanwhile, EGLN2 expression was negatively correlated with HIF1A expression in tumor tissues (r = -0.30, P = 4.78 × 10 -8 ) and significantly (P = 0.037) interacted with HIF1A expression on overall survival. Therefore, DNA methylation of EGLN2-HIF1A is a potential marker for LUAD prognosis and these genes are potential treatment targets for further development of HIF-1α inhibitors in lung cancer therapy.

YKT6 , as a potential predictor of prognosis and immunotherapy response for oral squamous cell carcinoma, is related to cell invasion, metastasis, and CD8+ T cell infiltration

“…The approaches were carried out as described previously. 28 The genes in the set with the lowest out-of-bagging (OOB) error were selected as candidate prognostic factors for further analysis.…”

Independent Validation of Early-Stage Non-Small Cell Lung Cancer Prognostic Scores Incorporating Epigenetic and Transcriptional Biomarkers With Gene-Gene Interactions and Main Effects

“… 6 , 7 In addition, gene-gene (G×G) interactions have long been recognized to regulate the progression of complex diseases, including NSCLC. 8 The development of cancer may be related to interactions between several key genes. 9 Lung cancer prognosis-associated biomarkers have been proposed on the basis of omics data, including DNA methylation, 10 gene expression, 11 microRNA, 12 and long noncoding RNA.…”

Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma

“…All patients provided written informed consent under the approval of the institutional review boards of each center. Data from the international study centers were harmonized as previously described [38–41]. Quality control procedures of DNA methylation and mRNA expression data are presented in Supplementary Material.…”