Integrated Analyses of m6A Regulator-Based Signature on Its Clinical Application and Immunogenomic Landscape in Stomach Adenocarcinoma

Abstract

Background. The whole tumor microenvironment (TME) infiltration features monitored by integrated roles of different RNA N6-methyladenosine (m6A) regulators remain elusive. Our study is aimed at exploring the association between m6A modification patterns, TME cell-infiltrating levels, and patients’ prognosis in stomach adenocarcinoma (STAD) patients. Methods. Consensus clustering was performed based on the integrated analyses of 17 m6A regulators and 229 m6A-related hallmark genes in STAD (The Cancer Genome Atlas (TCGA) cohort, $n=443$ ; Gene Expression Omnibus (GEO) GSE57303, $n=70$ , GSE62254 $n=300$ , and GSE84437 $n=433$ ). A m6ASig scoring system was calculated by the principal component analysis (PCA), and its prognostic value was validated in an independent dataset GES15459. Results. Three m6A clusters were identified among 1246 STAD patients, which had significant overall survival (OS) differences and demonstrated different TME immune cell infiltration and biological behaviors. According to the m6ASig score, which was generated from the m6A-related hallmark genes, STAD patients were divided into the high-m6ASig group ( $n=585$ ) and low-m6ASig group ( $n=586$ ). Patients in the high-m6ASig group had a notably prolonged OS and higher immune cell infiltration. Moreover, patients with higher m6ASig score were associated with higher microsatellite instability (MSI); higher PD-L1, CTLA4, and ERBB2 expressions; and greater tumor mutation burden (TMB). Patients with higher m6ASig score demonstrated a better immune response and drug sensitivity. Conclusion. Our m6ASig scoring system could characterize TME immune cell infiltration, thus predict patient’s prognosis and immunotherapy and chemotherapy efficacy, offering a novel tool for the individualized therapeutic implications for STAD patients.