Comprehensive Analysis of CDCAs Methylation and Immune Infiltrates in Hepatocellular Carcinoma

Abstract

BackgroundAs 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.MethodsWe 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.ResultA 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.ConclusionsThe 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.

Cell Division Cycle-Associated Genes Are Potential Immune Regulators in Nasopharyngeal Carcinoma

“…Notably, some studies have illuminated that CDCAs were associated with immune infiltration. Wang et al (28) suggested that CDCAs show a powerful association with immune function regulation in hepatocellular carcinoma (HCC). Wu et al (29) also indicated that CDCAs' expression was correlated with the abundance of immune infiltrates in head and neck squamous cell carcinoma (HNSCC).…”

“…Wang et al. ( 28 ) suggested that CDCAs show a powerful association with immune function regulation in hepatocellular carcinoma (HCC). Wu et al.…”

Biomarkers and Future Perspectives for Hepatocellular Carcinoma Immunotherapy

“…Another study identified a broad DNA methylation signature in peripheral blood mononuclear cells and T cells of HCC patients that differed from that of non-HCC patients (89). Additionally, differences in immune infiltrates related to the methylation levels of cell division cycle-associated (CDCA) family genes in HCC were reported to have potential as predictive biomarkers for responses to immunotherapy (90). Notably, Llopiz et al reported that an epigenetic drug/ICI combination exerted synergistic antitumor effects in a murine model of HCC (91), thereby providing further evidence that DNA methylation signatures may be related to the efficacy of immunotherapy, and also have the potential to serve as biomarkers of combination therapy.…”

“…Another study identified a broad DNA methylation signature in peripheral blood mononuclear cells and T cells of HCC patients that differed from that of non-HCC patients ( 89 ). Additionally, differences in immune infiltrates related to the methylation levels of cell division cycle-associated (CDCA) family genes in HCC were reported to have potential as predictive biomarkers for responses to immunotherapy ( 90 ). Notably, Llopiz et al.…”

Multidimensional study of CDCA family members in gastric carcinoma with prognostic value

“…The prognostic values of CDCAs are well documented in several cancers, including ovarian cancer, hepatocellular carcinoma, and endometrial carcinoma [ 19 - 21 ]. However, the function and prognostic utility of the CDCA family in GC, especially stomach adenocarcinoma (STAD), remain unknown and elusive.…”