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

Mol Oncol. 2022 Feb;16(3):717-731. doi: 10.1002/1878-0261.13167. Epub 2022 Jan 7.


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.

Keywords: DNA methylation; non-small-cell lung cancer; overall survival; prognostic prediction; three-way interaction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy-Related Proteins* / genetics
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / mortality
  • CpG Islands / genetics
  • DNA Methylation
  • DNA-Binding Proteins* / genetics
  • Epigenesis, Genetic
  • Epigenome
  • Genome-Wide Association Study
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / mortality
  • Nuclear Proteins* / genetics
  • Smoking* / genetics


  • Autophagy-Related Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RUBCN protein, human
  • TRIM27 protein, human