Genomics and Prognosis Analysis of N⁶-Methyladenosine Regulators in Lung Adenocarcinoma

Objective: N⁶-methyladenosine (m⁶A) modification is involved in modulating various biological processes in human cancers. But the implication of m⁶A modification in lung adenocarcinoma (LUAD) is still unclear. Hence, this study conducted a comprehensive analysis of the expression and clinical implication of m⁶A regulators in LUAD. Methods: Consensus clustering analysis of 502 LUAD samples in the TCGA dataset was presented based on the expression profiles of 20 m⁶A regulators using ConsensusClusterPlus package. Overall survival (OS), activation of signaling pathways and tumor immunity (immune/stromal score, tumor purity, expression of HLA and immune checkpoints, and immune cell infiltration) were compared between m⁶A modification patterns. The m⁶A-related genes between patterns were identified and prognostic m⁶A-related genes were imported into LASSO-cox regression analysis. The m⁶A risk score was developed and its prognostic implication was evaluated and externally verified in the GSE30219 and GSE72094 dataset. Furthermore, a nomogram that contained independent prognostic indicators was established, followed by external verification. Results: Two m⁶A modification patterns were clustered across LUAD based on the expression similarity of the m⁶A regulators via consensus clustering analysis, with distinct OS, activation of signaling pathways and tumor immunity. Totally, 213 m⁶A-related genes that were identified by comparing two patterns were significantly related to LUAD prognosis. By LASSO method, we constructed the m⁶A risk score that was a reliable and independent prognostic factor for LUAD. Patients with low m⁶A risk score displayed a prominent survival advantage. After incorporating independent clinical features, we developed the prognostic nomogram that exhibited high predictive accuracy and the best clinical net benefit for OS. Conclusion: Collectively, our study may provide a clinically useful tool for precise prognostic management and optimization of immunotherapeutic strategies for LUAD patients.