Identification of epigenetic dysregulation gene markers and immune landscape in kidney renal clear cell carcinoma by comprehensive genomic analysis

Abstract

Kidney cancer is one the most lethal cancers of the urinary system, but current treatments are limited and its prognosis is poor. This study focused on kidney renal clear cell carcinoma (KIRC) and analyzed the relationship between epigenetic alterations and KIRC prognosis, and explored the prognostic significance of these findings in KIRC patients. Based on multi-omics data, differentially expressed histone-modified genes were identified using the R package limma package. Gene enhancers were detected from data in the FANTOM5 database. Gene promoters were screened using the R package ChIPseeker, and the Bumphunter in the R package CHAMP was applied to screen differentially methylated regions (DMR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional enrichment analysis of genes was performed using the R package clusterProfiler. We identified 51 dysregulated epigenetic protein coding genes (epi-PCGs) from 872 epi-PCGs, and categorized three molecular subtypes (C1, C2, and C3) of KIRC samples with significantly different prognosis. Notably, among the three molecular subtypes, we found a markedly differential immune features in immune checkpoints, cytokines, immune signatures, and immune cell distribution. C2 subtype had significantly lower enrichment score of IFNγ, cytotoxic score (CYT), and angiogenesis. In addition, an 8-gene signature containing 8 epi-PCGs (ETV4, SH2B3, FATE1, GRK5, MALL, HRH2, SEMA3G, and SLC10A6) was developed for predicting KIRC prognosis. Prognosis of patients with a high 8-gene signature score was significantly worse than those with a low 8-gene signature score, which was also validated by the independent validation data. The 8-gene signature had a better performance compared with previous signatures of KIRC. Overall, this study highlighted the important role of epigenetic regulation in KIRC development, and explored prognostic epi-PCGs, which may provide a guidance for exploiting further pathological mechanisms of KIRC and for developing novel drug targets.

Keywords: epigenetic modification; histone-modified genes; kidney cancer; multi-omics data; prognosis.