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Epigenetics. 2019 Feb;14(2):118-129. doi: 10.1080/15592294.2019.1573066. Epub 2019 Jan 31.

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

Author information

1
a Department of Biostatistics , Center for Global Health, School of Public Health, Nanjing Medical University , Nanjing , Jiangsu , China.
2
b Department of Environmental Health , Harvard T.H. Chan School of Public Health , Boston , MA , USA.
3
c China International Cooperation Center for Environment and Human Health , Nanjing Medical University , Nanjing , Jiangsu , China.
4
d Department of Epidemiology and Biostatistics , School of Public Health, Southeast University , Nanjing , Jiangsu , China.
5
e Department of Biostatistics , Harvard T.H. Chan School of Public Health , Boston , MA , USA.
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f Pulmonary and Critical Care Division, Department of Medicine , Massachusetts General Hospital and Harvard Medical School , Boston , MA , USA.
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g Bellvitge Biomedical Research Institute and University of Barcelona and Institucio Catalana de Recerca i Estudis Avançats , Barcelona , Catalonia , Spain.
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h Department of Cancer Genetics , Institute for Cancer Research, Oslo University Hospital , Oslo , Norway.
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i Division of Oncology and Pathology, Department of Clinical Sciences Lund and CREATE Health Strategic Center for Translational Cancer Research , Lund University , Lund , Skåne , Sweden.
10
j Institute of Clinical Medicine , University of Oslo , Oslo , Norway.
11
k Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment , Cancer Center, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University , Nanjing , Jiangsu , China.

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 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-1α inhibitors in lung cancer therapy.

KEYWORDS:

; DNA methylation; lung cancer; prognosis

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