N⁶-methyladenosine (m⁶A) RNA methylation signature as a predictor of stomach adenocarcinoma outcomes and its association with immune checkpoint molecules

Objective: Although N⁶-methyladenosine (m⁶A) RNA methylation is the most common mRNA modification process, few studies have examined the role of m⁶A in stomach adenocarcinomas (STADs).

Methods: In this retrospective study, we analyzed 293 STAD samples from The Cancer Genome Atlas with complete clinicopathological feature profiles. The m⁶A methylation risk signature was derived from LASSO-Cox regression analyses with 15 m⁶A regulators. Statistical analysis was performed and figures were prepared using R software (https://www.R-project.org/).

Results: The m⁶A signature was established as follows: risk score = FTO × 0.127 + YTHDF1 × 0.004 + KIAA1429 × 0.044 + YTHDC2 × 0.112 - RBM15 × 0.135 - ALKBH5 × 0.019 - YTHDF2 × 0.028, which was confirmed as an independent prognostic indicator to predict overall survival of patients with STAD. Risk scores and tumor grades were closely associated. Cell cycle, p53 signaling pathways, DNA mismatch repair, and RNA degradation were enriched in the low-risk subgroup. This subgroup showed significantly higher expression of immune checkpoint molecules including PD-1 (programmed death 1), PD-L1 (programmed death-ligand 1), and CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4), suggesting that the signature may be a useful immunotherapy predictor.

Conclusions: We established an m⁶A methylation signature as an independent prognostic tool to predict overall survival, which may also be useful as an immunotherapy predictor.