Abstract 3483: Epigenome-wide association study of lung cancer among never-smokers in two prospective cohorts in Shanghai
Authors: Rahman Mohammad L. , Breeze Charles E. , Shu Xiao-Ou , Wong Jason YY , Cardenas Andres , Wang Xuting , Ji Bu-Tian , Hu Wei , Blechter Batel , Cai Qiuyin , Hosgood H Dean , Yang Gong , Shi Jianxin , Long Jirong , Gao Yu-Tang , Bell Douglas , Zheng Wei , Lan Qing , Rothman Nathaniel 
Published: April 2023

Abstract
Background: The etiology of lung cancer among never-smokers has not been adequately elucidated despite that globally15% of lung cancer cases in men and 53% in women are not smoking-related. Epigenetic modifications, including changes in DNA methylation (DNAm), have been suggested as possible underlying mechanisms. However, only a few prospective epigenome-wide association studies (EWAS) of lung cancer incidence have been conducted, all exclusively focused on DNAm in peripheral blood cells and included a minimal number of never-smokers. We aimed to investigate genome-wide DNAm associations and epigenetic age acceleration with future risk of lung cancer among never-smokers using pre-diagnostic oral rinse samples.
Methods: We conducted a case-control study of 80 never-smoking incident lung cancer cases and 83 comparable never-smoking controls nested in two large prospective cohorts: the Shanghai Women’s Health Study and Shanghai Men’s Health Study. DNAm was measured using the Illumina EPIC array. The top 50 differentially methylated positions (DMPs) were identified from a discovery sample and tested for replication in a validation sample using robust linear regression models. We also conducted an EWAS in the pooled sample. We examined functional overlap enrichment across chromatin states and histone mark broadPeaks for the top 1000 DMPs using eFORGE and constructed enrichment biological pathways analyses.
Results: Across discovery and pooled EWAS, we identified four DMPs associated with lung cancer at the epigenome-wide significance level of P&lt;8.0x10-8 (cg01411366: SLC9A10, P=7.23x10-08; cg00811020: NAA30, P=3.95x10-08; cg05658193: EIF2A, SERP1, P=5.02x10-08; and cg09198866: unannotated, P=5.39x10-09). The top 1000 DMPs were significantly enriched in epithelial regulatory regions and were associated with small GTPase-mediated signal transduction pathways. Furthermore, epigenetic age acceleration, measured by the GrimAge clock was prospectively associated with an increased risk of lung cancer (OR=1.19 per year of acceleration; 95% CI: 1.06-1.34) in logistic regression models.
Conclusions: To our knowledge, this is the first prospective EWAS of lung cancer among never-smokers using oral rinse samples. Our results show that DNAm in pre-diagnostic oral rinse samples can provide new insights into lung cancer etiology and risk factors.
Citation Format: Mohammad L. Rahman, Charles E. Breeze, Xiao-Ou Shu, Jason YY Wong, Andres Cardenas, Xuting Wang, Bu-Tian Ji, Wei Hu, Batel Blechter, Qiuyin Cai, H Dean Hosgood, Gong Yang, Jianxin Shi, Jirong Long, Yu-Tang Gao, Douglas Bell, Wei Zheng, Qing Lan, Nathaniel Rothman. Epigenome-wide association study of lung cancer among never-smokers in two prospective cohorts in Shanghai [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3483.