Abstract 5790: An epigenome-wide gene-age interaction analysis reveals opposite effects of PRODH DNA methylation on survival between young and elderly early-stage NSCLC patients

Abstract

Abstract Introduction: Aging has become a global public health concern. The number of elderly lung cancer patients increased and elderly comprise the majority (81%) of non-small cell lung cancer (NSCLC) patients. DNA methylation is a potential prognostic biomarker for NSCLC, while it is also associated with aging. However, whether the association between DNA methylation and NSCLC survival is modified by aging is not known. Methods: After quality control procedures, we used a two-stage study design to identify DNA methylation-age interaction that associated with overall survival (OS) for early-stage adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients from four international collaborating study centers. In the discovery phase, we investigated the interaction effect in LUAD and LUSC using Cox proportional hazards model, adjusted for covariates. We confirmed the significant interactions with Bonferroni adjusted P ≤ 0.05 were further confirmed in the validation phase using The Cancer Genome Atlas (TCGA) database. Results: A total of 1,230 LUAD and LUSC patients were eligible for the study and 311,981 DNA methylation loci were evaluated. There were 613 (NLUAD = 492 and NLUSC = 121) patients in the discovery phase, and 617 (NLUAD = 332 and NLUSC = 285) patients in the validation phase, respectively. We identified one LUAD-specific CpG probe cg14326354PRODH, the effect on OS was significantly modified by age (HRinteraction = 0.989; 95% CI: 0.986-0.994; P = 9.18 × 10−7). The effect of DNA methylation on OS was different in young and elderly patients (young: HR = 2.44; 95% CI: 1.26-4.72; P = 8.34 × 10−3; elderly: HR = 0.58; 95% CI: 0.42-0.82; P = 1.67 × 10−3). Low methylation level benefited elderly LUAD patients. Moreover, there was an antagonistic interaction between low methylation of cg14326354PRODH and elder age (HRinteraction = 0.21; 95% CI: 0.11-0.40; P = 2.20 × 10−6). Conclusion: Low methylation of cg14326354PRODH may benefit the survival of elderly LUAD patients, providing new insight into only age-specific prediction, but also potential methylation-specific drug targeting. Citation Format: Li Su. An epigenome-wide gene-age interaction analysis reveals opposite effects of PRODH DNA methylation on survival between young and elderly early-stage NSCLC patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5790.