Telomere-related gene signature as a prognostic and immunogenomic classifier in stomach adenocarcinoma

Objective: To profile telomere-related genes (TRGs) to develop a robust prognostic tool for stomach adenocarcinoma (STAD) and explore their associations with immune regulation and treatment response. Methods: A total of 2083 TRGs were analyzed in The Cancer Genome Atlas (TCGA)-STAD cohort (412 tumor and 36 normal samples) and external validation was performed using the GSE84437 dataset. A prognostic model was constructed through differential expression analysis, univariate Cox regression, and least absolute shrinkage and selection operator Cox regression. Model performance was evaluated using Kaplan–Meier survival analysis, multivariable Cox regression, time-dependent receiver operating characteristic curves, and nomogram construction. Associations with immune cell infiltration, tumor mutation burden (TMB), tumor immune dysfunction and exclusion (TIDE), and drug sensitivity were assessed. The expression patterns of the signature genes were experimentally validated using quantitative reverse transcription polymerase chain reaction and Western blot analysis in human gastric cancer cell lines and an N-methyl-N′-nitro-N-nitrosoguanidine induced rat gastric adenocarcinoma model. Results: An eight-TRG signature (ANXA5, ELOVL2, INCENP, NFE2L3, NOS3, RASGEF1C, REPIN1, and SOAT1) effectively predicted overall survival in the TCGA and GSE84437 cohorts, independent of clinicopathological factors (1-, 3-, and 5-year area under curves: 0.682, 0.695, and 0.697, respectively). The expression of seven genes were upregulated in tumor tissues, whereas that of RASGEF1C was downregulated. The derived risk score correlated with immune infiltration, TMB, and TIDE scores, and predicted drug sensitivities differed between the risk groups. Reverse transcription quantitative polymerase chain reaction analysis further validated the expression patterns of these genes in cell lines. In vitro and in vivo assays corroborated the bioinformatics findings, confirming the dysregulation of key signature genes in tumor cells and tissues at the mRNA and protein levels. Conclusions: The eight-TRG signature provides reliable prognostic stratification for STAD and links telomere biology to the immune context and therapy response.