Development and validation of a m⁶A -regulated prognostic signature in lung adenocarcinoma

Lung adenocarcinoma (LUAD) is the most frequent subtype of lung cancer, with a 5-year survival rate of less than 20%. N6-methyladenosine (m⁶A) is the most prevalent RNA epigenetic modification in eukaryotic cells, and post-transcriptionally regulates gene expression and function by affecting RNA metabolism. The alterations of functionally important m⁶A sites have been previously shown to play vital roles in tumor initiation and progression, but little is known about the extent to which m⁶A-regulated genes play in prognostic performance for patients with LUAD. Here, we presented an overview of the m⁶A methylome in LUAD tissues using transcriptome-wide m⁶A methylation profiles, and found that differentially methylated transcripts were significantly enriched in tumor-related processes, including immune response, angiogenesis and cell-substrate adhesion. Joint analysis of m⁶A modification and gene expression suggested that 300 genes were regulated by m⁶A. Furthermore, we developed a m⁶A-regulated prognosis-associated signature (m⁶A-PPS) by performing a multi-step process. The m⁶A-PPS model, a 15-gene set, was qualified for prognosis prediction for LUAD patients. By regrouping the patients with this model, the OS of the high-risk group was shorter than that of the low-risk group across all datasets. Importantly, patients with high m⁶A-PPS scores respond better to immunotherapeutic. Our results provide a valuable resource for understanding the important role of epitranscriptomic modifications in the pathogenesis of LUAD, and obtain potential prognostic biomarkers.