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

Xinyu Ji, Lijuan Lin, Juanjuan Fan, Yi Li, Yongyue Wei, Sipeng Shen, Li Su, Andrea Shafer, Maria Moksnes Bjaanæs, Anna Karlsson, Maria Planck, Johan Staaf, Åslaug Helland, Manel Esteller, Ruyang Zhang, Feng Chen, David C. Christiani

Research output: Contribution to journalArticlepeer-review

1 Citation (SciVal)

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.

Original languageEnglish
Pages (from-to)717-731
Number of pages15
JournalMolecular Oncology
Volume16
Issue number3
DOIs
Publication statusPublished - 2022 Feb

Subject classification (UKÄ)

  • Medical Genetics
  • Cancer and Oncology

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