Epigenome-wide gene–age interaction analysis reveals reversed effects of PRODH DNA methylation on survival between young and elderly early-stage NSCLC patients

DNA methylation changes during aging, but it remains unclear whether the effect of DNA methylation on lung cancer survival varies with age. Such an effect could decrease prediction accuracy and treatment efficacy. We performed a methylation–age interaction analysis using 1,230 early-stage lung adenocarcinoma patients from five cohorts. A Cox proportional hazards model was used to investigate lung adenocarcinoma and squamous cell carcinoma patients for methylation–age interactions, which were further confirmed in a validation phase. We identified one adenocarcinoma-specific CpG probe, cg14326354_PRODH, with effects significantly modified by age (HR_interaction = 0.989; 95% CI: 0.986–0.994; P = 9.18×10–7). The effect of low methylation was reversed for young and elderly patients categorized by the boundary of 95% CI standard (HR_young = 2.44; 95% CI: 1.26–4.72; P = 8.34×10-3; HR_elderly = 0.58; 95% CI: 0.42–0.82; P = 1.67×10-3). Moreover, there was an antagonistic interaction between low cg14326354_PRODH methylation and elderly age (HR_interaction = 0.21; 95% CI: 0.11–0.40; P = 2.20×10−6). In summary, low methylation of cg14326354PRODH might benefit survival of elderly lung adenocarcinoma patients, providing new insight to age-specific prediction and potential drug targeting.