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

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 (cg02268510(SIPA) (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 cg02268510(SIPA) (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 cg02268510(SIPA) (1L3). Moreover, there was an antagonistic interaction between elevated methylation of cg02268510(SIPA) (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 cg02268510(SIPA) (1L3). The results have implications for not only smoking cessation after diagnosis, but also possible methylation‐specific drug targeting.