Multi-omics analysis of tumor angiogenesis characteristics and potential epigenetic regulation mechanisms in renal clear cell carcinoma

Abstract

Background Tumor angiogenesis, an essential process for cancer proliferation and metastasis, has a critical role in prognostic of kidney renal clear cell carcinoma (KIRC), as well as a target in guiding treatment with antiangiogenic agents. However, tumor angiogenesis subtypes and potential epigenetic regulation mechanisms in KIRC patient remains poorly characterized. System evaluation of angiogenesis subtypes in KIRC patient might help to reveal the mechanisms of KIRC and develop more target treatments for patients. Method Ten independent tumor angiogenesis signatures were obtained from molecular signatures database (MSigDB) and gene set variation analysis was performed to calculate the angiogenesis score in silico using the Cancer Genome Atlas (TCGA) KIRC dataset. Tumor angiogenesis subtypes in 539 TCGA-KIRC patients were identified using consensus clustering analysis. The potential regulation mechanisms was studied using gene mutation, copy number variation, and differential methylation analysis (DMA). The master transcription factors (MTF) that cause the difference in tumor angiogenesis signals were completed by transcription factor enrichment analysis. Results The angiogenesis score of a prognosis related angiogenesis signature including 189 genes was significantly correlated with immune score, stroma score, hypoxia score, and vascular endothelial growth factor (VEGF) signal score in 539 TCGA KIRC patients. MMRN2, CLEC14A, ACVRL1, EFNB2, and TEK in candidate gene set showed highest correlation coefficient with angiogenesis score in TCGA-KIRC patients. In addition, all of them were associated with overall survival in both TCGA-KIRC and E-MTAB-1980 KIRC data. Clustering analysis based on 183 genes in angiogenesis signature identified two prognosis related angiogenesis subtypes in TCGA KIRC patients. Two clusters also showed different angiogenesis score, immune score, stroma score, hypoxia score, VEGF signal score, and microenvironment score. DMA identified 59,654 differential methylation sites between two clusters and part of these sites were correlated with tumor angiogenesis genes including CDH13, COL4A3, and RHOB. In addition, RFX2, SOX13, and THRA were identified as top three MTF in regulating angiogenesis signature in KIRC patients. Conclusion Our study indicate that evaluation the angiogenesis subtypes of KIRC based on angiogenesis signature with 183 genes and potential epigenetic mechanisms may help to develop more target treatments for KIRC patients.

Integrate analysis of the prognostic values of COL4As to human gastric cancer

“…COL4A3 is up-regulated in ovarian cancer [40]. And COL4A3 was an angiogenesis related gene of kidney renal clear cell carcinoma [41]. Besides, COL4A3 was a prognostic indicator of gastric carcinomas [42].…”

Metabolic Understanding of the Genetic Dysregulation in the Tumor Microenvironment of Kidney Renal Clear Cell Carcinoma

“…Previously, studies have estimated immune cell infiltration in the tumor microenvironment of several cancers. A relationship between tumor immune cells and angiogenesis in KIRC samples' data obtained from TCGA was studied, and RFX2, SOX13, and THRA were identified as the top three MTF in regulating angiogenesis signature in KIRC patients [ 4 ]. Moreover, two independent m6A modification patterns control biological functions, immunological characteristics, and prognoses of KIRC [ 22 ].…”

“…Recently, bioinformatics-based identification of the potential markers in cancers is being widely used but only few reliable biomarkers of KIRC have been identified or most of the markers are so far not fully validated. Thus, bioinformatics analyses coupled with experimental validations are necessary to elucidate the potential mechanism of the biogenesis and progression of KIRC [ 4 ]. Deep exploration of the tumor microenvironment and the development of immunotherapy have made it possible to study the interaction between tumor and the immune system [ 5 ].…”

The role of pro- and antiangiogenic factors in angiogenesis process by Raman spectroscopy

“…The process of formation new blood vessels is multi-stage. 1 2 3 In the first stage the stable vessels (Figure 1A) undergo a vascular permeability increase. This process allows extravasation of plasma proteins (Figure 1B).…”