Systematic Chromatin Accessibility Analysis Based on Different Immunological Subtypes of Clear Cell Renal Cell Carcinoma

Abstract

BackgroundRecent research of clear cell renal cell carcinoma (ccRCC) is focused on the tumor immune microenvironment (TIME). Chromatin accessibility is critical for regulation of gene expression. However, its role in different immunological subtypes of ccRCC based on immune cell infiltration has not been systematically studied.MethodsFive hundred thirty patient data from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) were adopted to estimate immune cell infiltration. Twenty-four types of immune cells were evaluated with single-sample Gene Set Enrichment Analysis (ssGSEA). Patients were divided into two clusters based on immune cell infiltration. Systematic chromatin accessibility analysis was conducted based on the two clusters.ResultsWe compared the relative expression of the immune gene signatures among 530 patients of TCGA-KIRC using ssGSEA. Overall survival (OS) analysis revealed 10 types of immune cells were significantly associated with prognosis. Patients were divided into two clusters based on 24 types of immune cell infiltration. Immune cell signals as well as PD-1/PD-L1 signal were higher in cluster 1. Among the two clusters, 2,400 differential peaks were found in TCGA-KIRC Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) data. The distribution of differential peaks and prognosis-related immune cells in 23 chromosomes are essentially the same. There is no peak distribution downstream. The proportion of peaks upstream of the 5’ transcription start site decreases, and both sides of binding regions of the TSS 0.1-1 kb becomes smaller. Enrichment analysis of GO and KEGG of these differential peaks showed that they are remarkably related to the immune regulation in tumor microenvironment. Known motifs and de novo motifs were found by linking motif annotations to different peaks. Survival analysis of related motif transcription factors were prognostic. The GSEA enrichment analysis showed that high SP1 expression positively correlates with TGF-beta signaling and inflammatory response, while negatively correlates with TNF-alpha signaling via NFKB. High KLF12 expression negatively correlates with interferon gamma response, IL2-STAT5 signaling, TNF-alpha signaling via NFKB, IL6-JAK-STAT3 signaling.ConclusionThe abnormality of chromatin accessibility may play an important regulatory role in ccRCC immunity.

Research Progress of Tumor Microenvironment Targeted Therapy for Clear Cell Renal Cell Carcinoma

“…Overall, ccRCC is characterized by increased inflammation and angiogenesis, which further promote tumor metastasis and recurrence. Shiqiang et al 62 analyzed 530 tumor samples and found that the existence of Tregs, activated DCs (aDCs), CD58 + NK cells, and Th2 cells was related to the poor prognosis of patients with ccRCC ( P < .05). Th17 cells, neutrophils, mast cells, NK cells, γδ T cells, and central memory T cells were associated with good prognosis in ccRCC ( P < .05).…”

Genomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort

“…Epigenomic aberrations in RCC have attracted increased attention recently 12 – 14 . In particular, chr.3p, whose loss is a typical genomic aberration in ccRCC, contains several chromatin modifiers, such as PBRM1, SETD2, and BAP1, and these genetic mutations are also frequently observed in the contralateral allele 15 , 16 .…”

Comprehensive Analysis of the Immune Cell Infiltration Landscape and Immune-Related Methylation in Retinoblastoma

“…Moreover, bioinformatics algorithms are developed for an immune infiltration estimation of a series of cancer tissues based on their transcriptional data ( Hänzelmann et al, 2013 ; Yoshihara et al, 2013 ; Newman et al, 2015 ). These methods have significantly promoted our understanding of the TME and have been applied to hepatocellular carcinoma ( Liu S. et al, 2021 ), clear cell renal cell carcinoma ( Zhang et al, 2021 ), pancreatic adenocarcinoma ( Liu et al, 2020 ), and so on. However, the application of retinoblastoma has not been fully elucidated.…”