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Comprehensive Analysis of the Immune Infiltrates and PD-L1 of m⁶A RNA Methylation Regulators in Hepatocellular Carcinoma.

ABSTRACT: Recently, N ⁶-methyladenosine (m⁶A) RNA methylation in eukaryotic mRNA has become increasingly obvious in the pathogenesis and prognosis of cancer. Moreover, tumor microenvironment is involved in the regulation of tumorigenesis. In our research, the clinical data, including 374 tumor and 50 normal patients, were obtained from The Cancer Genome Atlas (TCGA). Then 19 m⁶A regulators were selected from other studies. Hepatocellular carcinoma (HCC) patients were clustered in cluster1/2, according to the consensus clustering for the m⁶A RNA regulators. We found that m⁶A regulators were upregulated in cluster1. The cluster1 was associated with higher programmed death ligand 1 (PD-L1) expression level, higher immunoscore, worse prognosis, and distinct immune cell infiltration compared with cluster2. Five risk signatures were identified, including YTH N6-methyladenosine RNA-binding protein 1, YTHDF2, heterogeneous nuclear ribonucleoprotein C, WT1-associated protein, and methyltransferase-like 3, based on univariate Cox and least absolute shrinkage and selection operator regression analysis. High-risk group and low-risk group HCC patients were selected based on the risk score. Similarly, the high-risk group was extremely associated with higher PD-L1 expression level, higher grade, and worse overall survival (OS). Also, cluster1 was mainly enriched in high-risk group. Receiver operating characteristic (ROC) and a nomogram were used to predict the ability and the probability of 3- and 5-year OS of HCC patients. The time-dependent ROC curve (AUC) reached 0.77, 0.67, and 0.68 at 1, 3, and 5 years in the training dataset. Also, AUC areas of 1, 3, and 5 years were 0.7, 0.63, and 0.55 in the validation dataset. The gene set enrichment analysis showed that MTOR signaling pathway and WNT signaling pathway were correlated with cluster1 and high-risk group. Collectively, the research showed that the m⁶A regulators were significantly associated with tumor immune microenvironment in HCC. Risk characteristics based on m⁶A regulators may predict prognosis in patients with HCC and provide a new therapeutic target for improving the efficacy of immunotherapy.

SUBMITTER: Xu Y

PROVIDER: S-EPMC8277965 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most common cancer types and represents a threat to global public health. N6-Methyladenosine (m6A) methylation plays a key role in the occurrence and development of many tumors, but there are still few studies investigating ESCC. This study attempts to construct a prognostic signature of ESCC based on m6A RNA methylation regulators and to explore the potential association of these regulators with the tumor immune microenvironment (TIME).MethodsThe transcriptome sequencing data and clinical information of 20 m6A RNA methylation regulators in 453 patients with ESCC (The Cancer Genome Atlas [TCGA] cohort, n = 95; Gene Expression Omnibus [GEO] cohort, n = 358) were obtained. The differing expression levels of m6A regulators between ESCC and normal tissue were evaluated. Based on the expression of these regulators, consensus clustering was performed to investigate different ESCC clusters. PD-L1 expression, immune score, immune cell infiltration and potential mechanisms among different clusters were examined. LASSO Cox regression analysis was utilized to obtain a prognostic signature based on m6A RNA methylation modulators. The relationship between the risk score based on the prognostic signature and the TIME of ESCC patients was studied in detail.ResultsSix m6A regulators (METTL3, WTAP, IGF2BP3, YTHDF1, HNRNPA2B1 and HNRNPC) were observed to be significantly highly expressed in ESCC tissues. Two molecular subtypes (clusters 1/2) were determined by consensus clustering of 20 m6A modulators. The expression level of PD-L1 in ESCC tissues increased significantly and was significantly negatively correlated with the expression levels of YTHDF2, METL14 and KIAA1429. The immune score, CD8 T cells, resting mast cells, and regulatory T cells (Tregs) in cluster 2 were significantly increased. Gene set enrichment analysis (GSEA) shows that this cluster involves multiple hallmark pathways. We constructed a five-gene prognostic signature based on m6A RNA methylation, and the risk score based on the prognostic signature was determined to be an independent prognostic indicator of ESCC. More importantly, the prognostic value of the prognostic signature was verified using another independent cohort. m6A regulators are related to TIME, and their copy-number alterations will dynamically affect the number of tumor-infiltrating immune cells.ConclusionOur study established a strong prognostic signature based on m6A RNA methylation regulators; this signature was able to accurately predict the prognosis of ESCC patients. The m6A methylation regulator may be a key mediator of PD-L1 expression and immune cell infiltration and may strongly affect the TIME of ESCC.

Project description: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.

Project description:Gastric cancer is the fourth most frequent cancer and has a high death rate. Immunotherapy represented by PD-1 has brought hope for the treatment of advanced gastric cancer. Methylation of the m6A genes is linked to the onset and progression of numerous cancers, but there are few studies on gastric cancer. The main purpose of this study aims to analyze the relationship between m6A RNA methylation regulators, PD-L1, prognosis and tumor immune microenvironment (TIME) in gastric cancer. The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases were used to acquire transcriptomic data and clinical information from gastric cancer patients. The changes in m6A regulator expression levels in gastric cancer tissues and normal tissues were studied. Consensus clustering analysis was used to separate gastric cancer samples into two categories. We employed Least Absolute Shrinkage, Selection Operator (LASSO) Cox regression analysis, Gene Set Enrichment Analysis (GSEA), and cBioPortal to analyze the m6A regulators, PD-L1 and TIME in gastric cancer. In gastric cancer tissues, the majority of m6A regulatory factors are considerably overexpressed. Two gastric cancer subgroups (Cluster1/2) based on consensus clustering of 21 m6A regulators. PD-L1 and PD-1 expression levels were significantly higher in gastric cancer tissues, and they were significantly linked with METTL3, WTAP, HNRNPD, ZC3H7B, METTL14, FTO, PCIF1, HNRNPC, YTHDF1 and YTDHF2. Cluster1 showed a large increase in resting memory CD4+ T cells, regulatory T cells, naïve B cells, active NK cells, and resting Mast cells. Cluster1 and Cluster2 were shown to be involved in numerous critical signaling pathways, including base excision repair, cell cycle, nucleotide excision repair, RNA degradation, and spliceosome pathways. Gastric cancer RiskScores based on prognostic factors have been found as independent prognostic indicators. The amount of tumor-infiltrating immune cells is dynamically affected by changes in the copy number of m6A methylation regulators associated with TIME.

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Comprehensive Analysis of the Immune Infiltrates and PD-L1 of m⁶A RNA Methylation Regulators in Hepatocellular Carcinoma.

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Comprehensive Analysis of the Immune Infiltrates and PD-L1 of m6A RNA Methylation Regulators in Hepatocellular Carcinoma.

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OmicsDI is part of the ELIXIR infrastructure

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Comprehensive Analysis of the Immune Infiltrates and PD-L1 of m⁶A RNA Methylation Regulators in Hepatocellular Carcinoma.