Investigation of biomarkers associated with pathological stage of esophageal adenocarcinoma by integrating co-expression network and differential methylation analysis

Hua-Fei Chen¹, Xiao-Feng Li¹, Gang Lan¹, Li-Chao Huang1, Zhan-Qiang Zhai¹, You-Cai Zhu¹, Wen-Xian Wang², Chun-Wei Xu³, Xiao He^4* And Kai-Qi Du¹

¹Department of Thoracic Disease Center, Zhejiang Rongjun Hospital, Jiaxing, Zhejiang, 314000, China - ²Department of Chemotherapy, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China - ³Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350014, China - ⁴Department of Radiotherapy, Lishui People's Hospital, Lishui, Zhejiang, 323000, China

Background: Esophageal adenocarcinoma (EAC) is a devastating disease which related to a poor prognosis. Although many efforts have been paid to investigate the progress of EAC, pivotal molecular mechanism involved in the treatment of different tumor stages remains to be demonstrated. 

Materials and methods: We employ weighted correlation network analysis (WGCNA) and chip analysis methylation pipeline to explore core molecules associated with pathological staging by integrating gene expression and methylation profiles. By constructing a co-expression gene network, we screen out a gene set whose co-expression patterns are related to advanced stages of EAC. 

Results: Genes affected by abnormal methylation status are recognized by comparing differential methylation sites between cancer tissues and adjacent tissues, which can be distinguished by methylation levels. Based on integrative analysis on epigenetics and transcriptomics, we identified ten co-expressed genes accompanied with differential methylation. Expression levels of 3 genes including EGR2, HOXD8, and RSPO3, are identified to be negatively correlated with methylation values and to be associated with different pathological staging of EAC. These key genes promote tumorigenesis and cell proliferation by altering transcription factors activity and Wnt signaling pathway. 

Conclusions: Our study provides new insights into discovering characteristic molecules for divergent stages of EAC, which helps to optimize treatment of variable stages.