Epigenome‐wide three‐way interaction study identifies a complex pattern between TRIM27, KIAA0226, and smoking associated with overall survival of early‐stage NSCLC

• Published in: Molecular oncology Vol. 16; no. 3; pp. 717 - 731
• Main Authors: Ji, Xinyu, Lin, Lijuan, Fan, Juanjuan, Li, Yi, Wei, Yongyue, Shen, Sipeng, Su, Li, Shafer, Andrea, Bjaanæs, Maria Moksnes, Karlsson, Anna, Planck, Maria, Staaf, Johan, Helland, Åslaug, Esteller, Manel, Zhang, Ruyang, Chen, Feng, Christiani, David C.
• Format: Journal Article
• Language: English; Norwegian
• Published: United States John Wiley & Sons, Inc 01.02.2022; John Wiley and Sons Inc; Wiley
• Subjects: Analysis; Autophagy-Related Proteins - genetics; Basic Medicine; Biotechnology industry; Cancer and Oncology; Cancer och onkologi; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Cell survival; Cigarettes; Clinical Medicine; CpG islands; CpG Islands - genetics; Deoxyribonucleic acid; DNA; DNA Methylation; DNA probes; DNA-Binding Proteins - genetics; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Epigenome; Gene expression; Genome-Wide Association Study; Genomes; Humans; Klinisk medicin; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Mortality; Non-small cell lung carcinoma; non‐small‐cell lung cancer; Norway; Nuclear Proteins - genetics; overall survival; Patient outcomes; Prediction models; prognostic prediction; Quality control; Smoking; Smoking - genetics; Spain; Squamous cell carcinoma; Sweden; Therapeutic targets; three‐way interaction; Tumors; United States; Sweden; United States; Norway; Spain; prognostic prediction; DNA methylation; overall survival; three-way interaction; non-small-cell lung cancer
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13167

The interaction between DNA methylation of tripartite motif containing 27 (cg05293407TRIM27) and smoking has previously been identified to reveal histologically heterogeneous effects of TRIM27 DNA methylation on early‐stage non‐small‐cell lung cancer (NSCLC) survival. However, to understand the complex mechanisms underlying NSCLC progression, we searched three‐way interactions. A two‐phase study was adopted to identify three‐way interactions in the form of pack‐year of smoking (number of cigarettes smoked per day × number of years smoked) × cg05293407TRIM27 × epigenome‐wide DNA methylation CpG probe. Two CpG probes were identified with FDR‐q ≤ 0.05 in the discovery phase and P ≤ 0.05 in the validation phase: cg00060500KIAA0226 and cg17479956EXT2. Compared to a prediction model with only clinical information, the model added 42 significant three‐way interactions using a looser criterion (discovery: FDR‐q ≤ 0.10, validation: P ≤ 0.05) had substantially improved the area under the receiver operating characteristic curve (AUC) of the prognostic prediction model for both 3‐year and 5‐year survival. Our research identified the complex interaction effects among multiple environment and epigenetic factors, and provided therapeutic target for NSCLC patients. We performed a two‐phase designed epigenome‐wide three‐way gene‐smoking interaction study of NSCLC survival and identified two CpG probes (cg00060500KIAA0226 and cg17479956EXT2), together with pack‐year of smoking and cg05293407TRIM27, exhibiting significant three‐way interaction effects. Meanwhile, these significant three‐way interactions substantially improved the area under the receiver operating characteristic curve (AUC) of the prognostic prediction model for both 3‐ and 5‐year survival.