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

Zhang, Ruyang; Lai, Linjing; Dong, Xuesi; He, Jieyu; You, Dongfang; Chen, Chao; Lin, Lijuan; Zhu, Ying; Huang, Hui and Shen, Sipeng, et al. (2019) In Molecular Oncology 13(5). p.1235-1248
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... (More)


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.

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Please use this url to cite or link to this publication:
@article{59013cac-2605-442a-9444-0e8e84953b83,
  abstract     = {<p><br>
                                                         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                             <br>
                            <sub>SIPA</sub><br>
                                                         <br>
                            <sub>1L3</sub><br>
                                                         ) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR)                             <br>
                            <sub>interaction</sub><br>
                                                          = 1.12; 95% confidence interval (CI): 1.07–1.16; P = 4.30 × 10                             <br>
                            <sup>–7</sup><br>
                                                         ]. Further, the effect of smoking cessation on early-stage LUAD survival varied across patients with different methylation levels of cg02268510                             <br>
                            <sub>SIPA</sub><br>
                                                         <br>
                            <sub>1L3</sub><br>
                                                         . Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34–0.82; P = 4.61 × 10                             <br>
                            <sup>–3</sup><br>
                                                         ) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86–1.70; P = 0.266) of cg02268510                             <br>
                            <sub>SIPA</sub><br>
                                                         <br>
                            <sub>1L3</sub><br>
                                                         . Moreover, there was an antagonistic interaction between elevated methylation of cg02268510                             <br>
                            <sub>SIPA</sub><br>
                                                         <br>
                            <sub>1L3</sub><br>
                                                          and smoking cessation (HR                             <br>
                            <sub>interaction</sub><br>
                                                          = 2.1835; 95% CI: 1.27–3.74; P = 4.46 × 10                             <br>
                            <sup>−3</sup><br>
                                                         ). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510                             <br>
                            <sub>SIPA</sub><br>
                                                         <br>
                            <sub>1L3</sub><br>
                                                         . The results have implications for not only smoking cessation after diagnosis, but also possible methylation-specific drug targeting.                         <br>
                        </p>},
  author       = {Zhang, Ruyang and Lai, Linjing and Dong, Xuesi and He, Jieyu and You, Dongfang and Chen, Chao and Lin, Lijuan and Zhu, Ying and Huang, Hui and Shen, Sipeng and Wei, Liangmin and Chen, Xin and Guo, Yichen and Liu, Liya and Su, Li and Shafer, Andrea and Moran, Sebastian and Fleischer, Thomas and Bjaanæs, Maria Moksnes and Karlsson, Anna and Planck, Maria and Staaf, Johan and Helland, Åslaug and Esteller, Manel and Wei, Yongyue and Chen, Feng and Christiani, David C.},
  issn         = {1574-7891},
  keyword      = {DNA methylation,interaction analysis,molecular cancer epidemiology,non-small-cell lung cancer,overall survival,smoking cessation},
  language     = {eng},
  number       = {5},
  pages        = {1235--1248},
  publisher    = {Elsevier},
  series       = {Molecular Oncology},
  title        = {SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival : an epigenomic–smoking interaction analysis},
  url          = {http://dx.doi.org/10.1002/1878-0261.12482},
  volume       = {13},
  year         = {2019},
}