SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival: an epigenomic-smoking interaction analysis.

Ruyang Zhang,Sipeng Shen,Thomas Fleischer,Xin Chen,Yongyue Wei,Maria Planck,Chao Chen,David C Christiani,Anna Karlsson,Maria Moksnes Bjaanæs,Lijuan Lin,Jieyu He,Yichen Guo,Li Su,Liya Liu,Xuesi Dong,Åslaug Helland,Dongfang You,Liangmin Wei,Ying Zhu,Hui Huang,Feng Chen,Manel Esteller,Johan Staaf,Lihui Lai ,Andrea T Shafer ,Sebastián Morán

doi:10.1002/1878-0261.12482

Abstract

Smoking cessation prolongs survival and decreases mortality of patients with non‐small‐cell lung cancer (NSCLC). In addition, epigenetic alterations of some genes are associated with survival. However, potential interactions between smoking cessation and epigenetics have not been assessed. Here, we conducted an epigenome‐wide interaction analysis between DNA methylation and smoking cessation on NSCLC survival. We used a two‐stage study design to identify DNA methylation–smoking cessation interactions that affect overall survival for early‐stage NSCLC. The discovery phase contained NSCLC patients from Harvard, Spain, Norway, and Sweden. A histology‐stratified Cox proportional hazards model adjusted for age, sex, clinical stage, and study center was used to test DNA methylation–smoking cessation interaction terms. Interactions with false discovery rate‐q ≤ 0.05 were further confirmed in a validation phase using The Cancer Genome Atlas database. Histology‐specific interactions were identified by stratification analysis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. We identified one CpG probe (cg02268510SIPA 1L3) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR)interaction = 1.12; 95% confidence interval (CI): 1.07–1.16; P = 4.30 × 10–7]. Further, the effect of smoking cessation on early‐stage LUAD survival varied across patients with different methylation levels of cg02268510SIPA 1L3. Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34–0.82; P = 4.61 × 10–3) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86–1.70; P = 0.266) of cg02268510SIPA 1L3. Moreover, there was an antagonistic interaction between elevated methylation of cg02268510SIPA 1L3 and smoking cessation (HR interaction = 2.1835; 95% CI: 1.27–3.74; P = 4.46 × 10−3). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510SIPA 1L3. The results have implications for not only smoking cessation after diagnosis, but also possible methylation‐specific drug targeting.

Highlights

Lung cancer is a leading cause of cancer mortality worldwide
15 methylation–smoking cessation interactions were identified with false discovery rate (FDR)-q ≤ 0.05 (Fig. S2A), and the Manhattan plot showed the results for main effect (Fig. S2B)
Further histology-stratified analysis showed that cg02268510SIPA1L3 is a lung adenocarcinoma (LUAD)-specific CpG probe that interacts with smoking cessation to affect patient survival in the discovery phase (HRinteraction = 1.10; 95% confidence interval (CI): 1.05–1.16; P = 2.95 9 10–5), the validation phase (HRinteraction = 1.17; 95% CI: 1.02–1.35; P = 0.0255), and the combined data (HRinteraction = 1.12; 95% CI: 1.07–1.16; P = 4.30 9 10–7)

Summary

Introduction

Lung cancer is a leading cause of cancer mortality worldwide. In the United States, lung cancer was estimated as likely to account for 154 050 deaths in 2018, or one-fourth of all cancer deaths (Siegel et al, 2017). A large proportion of lung cancer cases are attributed to smoking, a well-known risk factor (Flanders et al, 2003), and smoking cessation prolongs survival and decreases mortality of lung cancer patients (Balduyck et al, 2011; Parsons et al, 2010). DNA methylation, a reversible epigenetic modification, regulates gene expression and provides potential cancer biomarkers and therapeutic targets (Egger et al, 2004; Feinberg and Tycko, 2004), including for non-small-cell lung cancer (NSCLC) (Guo et al, 2018; Shen et al, 2018; Wei et al, 2018). As a potential mechanistic link between cigarette smoking and disease, DNA methylation changes can result from various environmental exposures and may explain part of the association between smoking and cancer recurrence or mortality (Lee and Pausova, 2013; Shui et al, 2016)

Methods

Results

Conclusion