Comprehensive Analysis of Clinical Significance, Immune Infiltration and Biological Role of m6A Regulators in Early-Stage Lung Adenocarcinoma.
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ABSTRACT:
SUBMITTER: Zhou B
PROVIDER: S-EPMC8505809 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epigenetic modifications, especially N6-methyladenosine (m6A) modification, play a key role in tumor microenvironment (TME) infiltration. However, the regulatory role of m6A modification in the TME of lung adenocarcinoma (LUAD) remains unclear. A total of 2506 patients with LUAD were included in the analysis and divided into different groups according to distinct m6A modification-related patterns based on 23 m6A regulators. A comprehensive analysis was performed to explore TME infiltration in different m6A modification-related patterns. Principal component analysis was performed to obtain the m6Ascore and to quantify m6A modification-related patterns in different individuals. Three distinct m6A modification-related patterns were identified by 23 m6A regulators. The pathway enrichment analysis showed that m6Acluster-A was associated with immune activation; m6Acluster-B was associated with carcinogenic activation; m6Acluster-C was prominently related to substance metabolism. M6Acluster-A was remarkably rich in TME-infiltrating immune cells and patients with this pattern showed a survival advantage. The m6Ascore could predict TME infiltration, tumor mutation burden (TMB), the effect of tumor immunotherapy, and the prognosis of patients in LUAD. High m6Ascore was characterized by increased TME infiltration, reduced TMB, and survival advantage. Patients with a high m6Ascore exhibited significantly improved clinical response to anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA4) immunotherapy. This study explored the regulatory mechanisms of TME infiltration in LUAD. The comprehensive analysis of m6A modification-related patterns may contribute to the development of individualized immunotherapy and the improvement of the overall effectiveness of immunotherapy for LUAD patients.
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Project description:BACKGROUND The exact mechanisms of lung adenocarcinoma (LUAD) etiology and pathogenesis remain unclear. MATERIAL AND METHODS In this study, we evaluated alternative splicing (AS) events in LUAD. We separately analyzed LUAD data from The Cancer Genome Atlas (TCGA) database and AS-related feature lists from SpliceSeq to develop risk models for AS events and further validated risk models for AS events. The association between immune-related features and the risk model of AS events was evaluated. RESULTS We found that exon skip (ES) and mutually exclusive exons (ME) exhibited the most and least AS events, respectively. The risk score and stage of LUAD patients were strongly associated with prognosis and were independent influences on the prognosis of LUAD. The pathological stage (stage, T, N) and risk model were incorporated to construct a column line graph with better predictive ability. Risk models were associated with tumor microenvironment, and higher risk score values were associated with higher M2 macrophage content and lower M0 macrophage and helper T lymphocyte content. The correlation between core genes and immunity was further assessed by analyzing differentially-expressed genes between risk models. These results suggest an association between the level of risk for AS events and the density of immune cell infiltration. CONCLUSIONS Our findings suggest a clear association between AS risk model and patient prognosis, and was performed to confirm the biological relationship between AS and immunity.
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