Identification of the Signature Associated with m6A RNA Methylation Regulators and m6A-Related Genes and Construction of the Risk Score for Prognostication in Early-Stage Lung Adenocarcinoma

Abstract Background: N6-methyladenosine (m6A) RNA modification play critical roles in multiple levels including the regulation of degradation, subcellular localization, splicing and local conformation changes of RNA transcripts. In this study, we aim to conduct comprehensive investigation on m6A RNA methylation regulators and m6A-related genes and their association with prognosis in early-stage Lung adenocarcinoma (LUAD). Methods: The relevant datasets which were used to analyze 21 m6A RNA methylation regulators and 887 m6A-related genes in m6Avar were downloaded from Gene Expression Omnibus database (GEO) and The Cancer Genome Atlas (TCGA) databases. Univariate cox regression analysis, random survival forest analysis, Kaplan-Meier anylysis, STRING and multivariate cox analysis were carried out, and a risk prognostic model based on five feature genes was constructed. Respectively, we treated GSE31210 (n=226) as training set, GSE50081 (n=128) and TCGA data (n=461) as test set. Results: By performing univariable cox regression and random survival forest algorithm in the training group, five prognosis-related genes including DENND1A, KBTBD6, KIF4A, BMPER, and YTHDC2 were screened out, which could divide LUAD patients into low-risk group and high-risk group (log rank p <0.001). The predictive efficacy of these genes was confirmed in the test group GSE50081 (log rank p <0.01) and TCGA datasets (log rank p <0.001). Cox analysis showed that this five-gene signature was an independent risk factor in LUAD. Further, genes in the signature were also external validated using online database. YTHDC2 played vital role of readers in m6A methylation. Conclusions: The findings of this study suggested that associated with m6A-related genes and m6A RNA methylation regulators, five-gene signature was reliable prognostic indicator for LUAD patients, indicating a clinical application prospect to serve as a potential therapeutic target.