Comprehensive Analysis of CDCAs Methylation and Immune Infiltrates in Hepatocellular Carcinoma

Yongkang Wang; Yinfeng Yang; Honglei Gao; Ting Ouyang; Luyao Zhang; Jili Hu; Sheng Hu; Hongxing Kan

doi:10.3389/fonc.2020.566183

Comprehensive Analysis of CDCAs Methylation and Immune Infiltrates in Hepatocellular Carcinoma

Front Oncol. 2021 Feb 16:10:566183. doi: 10.3389/fonc.2020.566183. eCollection 2020.

Authors

Yongkang Wang¹, Yinfeng Yang^{1

2}, Honglei Gao¹, Ting Ouyang¹, Luyao Zhang¹, Jili Hu¹, Sheng Hu¹, Hongxing Kan^{1

2}

Affiliations

¹ School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, China.
² Anhui Computer Application Research Institute of Chinese Medicine, China Academy of Chinese Medical Sciences, Hefei, China.

Abstract

Background: As essential components of cycle growth, the cell division cycle-associated family genes (CDCAs) have crucial roles in tumor development and progression, especially in hepatocellular carcinoma (HCC). However, due to the tumor heterogeneity of HCC, little is known about the methylation variability of CDCAs in mediating phenotypic changes (e.g., immune infiltrates) in HCC. Presently, we aim to comprehensively explore the expression and prognosis of CDCAs methylation with regard to immune infiltrates of HCC.

Methods: We first identified the correlating differentially expressed genes (co-DEGs) among 19 different types of cancer cohorts (a total of 7,783 patients) and then constructed the weighted gene co-expressed and co-methylated networks. Applying the clustering analysis, significant modules of DEGs including CDCAs were selected and their functional bioinformatics analyses were performed. Besides, using DiseaseMeth and TIMER, the correlation between the methylation levels of CDCAs and tumor immune infiltrates was also analyzed. In final, to assess the influence of CDCAs methylation on clinical prognosis, Kaplan-Meier and Cox regression analysis were carried out.

Result: A total of 473 co-DEGs are successfully identified, while seven genes of CDCAs (CDCA1-3 and CDCA5-8) have significant over-expression in HCC. Co-expressed and co-methylated networks reveal the strong positive correlations in mRNA expression and methylation levels of CDCAs. Besides, the biological enrichment analysis of CDCAs demonstrates that they are significantly related to the immune function regulation of infiltrating immune cells in HCC. Also, the methylation analysis of CDCAs depicts the strong association with the tumor immunogenicity, i.e., low-methylation of CDCA1, CDCA2, and CDCA8 dramatically reduced the immune infiltrate levels of T cells and cytotoxic lymphocytes. Additionally, CDCA1-6 and CDCA8 with low-methylation levels significantly deteriorate the overall survival of patients in HCC.

Conclusions: The co-expressed and co-methylated gene networks of CDCAs show a powerful association with immune function regulation. And the methylation levels of CDCAs suggesting the prognostic value and infiltrating immune differences could be a novel and predictive biomarker for the response of immunotherapy.

Keywords: CDCA; DNA methylation; hepatocellular carcinoma; immune infiltrates; predictive biomarker.