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

• Published in: Molecular oncology 2019-05, Vol.13 (5), p.1235-1248
• Main Authors: Zhang, Ruyang, Lai, Linjing, Dong, Xuesi, He, Jieyu, You, Dongfang, Chen, Chao, Lin, Lijuan, Zhu, Ying, Huang, Hui, Shen, Sipeng, Wei, Liangmin, Chen, Xin, Guo, Yichen, Liu, Liya, Su, Li, Shafer, Andrea, Moran, Sebastian, Fleischer, Thomas, Bjaanæs, Maria Moksnes, Karlsson, Anna, Planck, Maria, Staaf, Johan, Helland, Åslaug, Esteller, Manel, Wei, Yongyue, Chen, Feng, Christiani, David C.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Analysis; Biomarkers; Biotechnology industry; Cancer and Oncology; Cancer och onkologi; Cancer patients; Cell survival; Cigarette smoking; Clinical Medicine; Confidence intervals; CpG islands; Deoxyribonucleic acid; Disease-Free Survival; DNA; DNA Methylation; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Drug addiction; Epigenetic inheritance; Epigenetics; Epigenomics; Female; Gene expression; Genome-Wide Association Study; Genomes; Genomic analysis; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Health aspects; Histology; Hospitals; Humans; interaction analysis; International economic relations; Klinisk medicin; Lung cancer; Lung carcinoma; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Methylation; Middle Aged; molecular cancer epidemiology; Mortality; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Non-small cell lung carcinoma; non-small-cell lung cancer; overall survival; Quality control; Review boards; Sensitivity analysis; Smoking - genetics; Smoking - metabolism; Smoking - mortality; Smoking - pathology; Smoking Cessation; Smoking cessation programs; Squamous cell carcinoma; Standard deviation; Studies; Survival Rate
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.12482

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 (cg02268510SIPA1L3) 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 cg02268510SIPA1L3. 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 cg02268510SIPA1L3. Moreover, there was an antagonistic interaction between elevated methylation of cg02268510SIPA1L3 and smoking cessation (HRinteraction = 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 cg02268510SIPA1L3. The results have implications for not only smoking cessation after diagnosis, but also possible methylation‐specific drug targeting. Though smoking cessation tends to benefit lung cancer patient survival, inconsistent results were reported from multiple studies, which may be due to heterogeneous epigenetic background. In this study, we identified an epigenetic modification at signal‐induced proliferation‐associated 1‐like 3 gene which highlights the benefit of smoking cessat