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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-1? 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 cg25923056EGLN2 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-1? inhibitors in lung cancer therapy.

SUBMITTER: Zhang R

PROVIDER: S-EPMC6557590 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Zhang Ruyang R Lai Linjing L He Jieyu J Chen Chao C You Dongfang D Duan Weiwei W Dong Xuesi X Zhu Ying Y Lin Lijuan L Shen Sipeng S Guo Yichen Y Su Li L Shafer Andrea A Moran Sebastian S Fleischer Thomas T Bjaanæs Maria Moksnes MM Karlsson Anna A Planck Maria M Staaf Johan J Helland Åslaug Å Esteller Manel M Wei Yongyue Y Chen Feng F Christiani David C DC

Epigenetics 20190131 2

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 ...[more]

PMID: 30665327

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Project description:BackgroundIt was demonstrated that multifunctional protein APE1 (Apurinic/apyrimidinic endonuclease 1) is closely related to tumor immune microenvironment in a number of investigations, Meanwhile, the abundance of tumor infiltrating lymphocytes (TILs) has been shown as a prognosis indicator in some researches. However, it remains unclear whether APE1 is involved in the process of TILs affecting the prognosis of patients. To this end, we investigated the associations between APE1 and TILs in non-small cell lung cancer (NSCLC) and explored whether APE1 would influence the associations of CD4+ T cells infiltration with the prognosis of patients.MethodsGenome-wide expression datasets were obtained from the Gene Expression Omnibus (GEO) public database under accession number GSE68465, GSE30219, GSE31210 and GSE50081. MCPcounter and CIBERSORT analysis was conducted to evaluate the abundance of TILs in 1006 NSCLC patients of GEO database. Spearman correlation tests were used to evaluate correlations between abundance of various TILs and APE1 expression. RFS (recurrence free survival) was estimated using the Kaplan-Meier method and the Cox proportional-hazards model. The expression level of APE1 and tumor-infiltrating CD4+ T cells was evaluated by immunohistochemistry (IHC).ResultsThe results showed that the abundance of CD4+ naïve T cells was negatively associated with the APE1 expression. CD4+ naïve T cells infiltration was a favorable prognostic factor for RFS, however, there was no effect of CD4+ T cells infiltration on RFS in patients with high APE1 expression. Subsequently, it was further confirmed that CD4+ T cells infiltration was negatively associated with the APE1 expression level in 108 NSCLC tissue samples; high CD4+ T cells infiltration was associated with longer RFS in low APE1 expression group but not in APE1 high expression group.ConclusionThese results suggested that APE1 may affect the relationship between CD4+ T cells infiltration and prognosis in NSCLC. This study provides new insights into predictors of outcome in patients with NSCLC, and suggests that combining immunotherapy and APE1-targeted therapy may be a promising treatment for NSCLC.

Dataset Information

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

Publications

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

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