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

Abstract

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.