Epigenome-wide gene-age interaction study reveals reversed effects of MORN1 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(MORN1), whose effect was significantly modified by age (HRdiscovery = 1.018, p = 4.07 x 10(-07), FDR-q = 3.67 x 10(-02); HRvalidation = 1.058, p = 8.09 x 10(-03); HRcombined = 1.019, p = 7.36 x 10(-10)). Moreover, there was an antagonistic interaction between hypomethylation of cg11676291(MORN1) and age (HRinteraction = 0.284; 95% CI, 0.135-0.597; p = 9.04 x 10(-04)). The prognosis of OSCC patients was well discriminated by the prognostic score incorporating cg11676291(MORN1)-age interaction (HRhigh vs. low = 3.66, 95% CI: 2.40-5.60, p = 1.93 x 10(-09)). 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(3-year) = 0.80, AUC(5-year) = 0.79, C-index = 0.75). Our study identified a significant interaction between cg11676291(MORN1) and age on OSCC survival, providing a potential therapeutic target for OSCC patients.

Automated summary

We found that the effect of DNA methylation on oral squamous cell carcinoma (OSCC) survival varies with age, with cg11676291 (MORN1) being significantly modified by age. The prognostic score incorporating cg11676291(MORN1)-age interaction can well discriminate the prognosis of OSCC patients.