Epigenome-wide gene-age interaction study reveals reversed effects of DNA methylation on survival between young and elderly oral squamous cell carcinoma patients.

DNA methylation serves as a reversible and prognostic biomarker for oral squamous cell carcinoma (OSCC) patients. It is unclear whether the effect of DNA methylation on OSCC overall survival varies with age. As a result, we performed a two-phase gene-age interaction study of OSCC prognosis on an epigenome-wide scale using the Cox proportional hazards model. We identified one CpG probe, cg11676291 , whose effect was significantly modified by age (HR = 1.018, = 4.07 × 10, FDR- = 3.67 × 10; HR = 1.058, = 8.09 × 10; = 1.019, = 7.36 × 10). Moreover, there was an antagonistic interaction between hypomethylation of cg11676291 and age (HR = 0.284; 95% CI, 0.135-0.597; = 9.04 × 10). The prognosis of OSCC patients was well discriminated by the prognostic score incorporating cg11676291 -age interaction ( = 3.66, 95% CI: 2.40-5.60, = 1.93 × 10). By adding 24 significant gene-age interactions using a looser criterion, we significantly improved the area under the receiver operating characteristic curve (AUC) of the model at 3- and 5-year prognostic prediction (AUC = 0.80, AUC = 0.79, C-index = 0.75). Our study identified a significant interaction between cg11676291 and age on OSCC survival, providing a potential therapeutic target for OSCC patients.