Epigenetic modifications inlysine demethylases associate with survival of early-stage NSCLC

Research output: Contribution to journalArticle

Abstract

Background: KDMlysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations inKDMgenes and their roles in lung cancer survival.

Methods: Tumor tissue samples of 1230 early-stage non-small cell lung cancer (NSCLC) patients were collected from the five independent cohorts. The 393 methylation sites inKDMgenes were extracted from epigenome-wide datasets and analyzed by weighted random forest (Ranger) in discovery phase and validation dataset, respectively. The variable importance scores (VIS) for the sites in top 5% of both discovery and validation sets were carried forward for Cox regression to further evaluate the association with patient's overall survival. TCGA transcriptomic data were used to evaluate the correlation with the corresponding DNA methylation.

Results: DNA methylation at sites cg11637544 inKDM2Aand cg26662347 inKDM1Awere in the top 5% of VIS in both discovery phase and validation for squamous cell carcinomas (SCC), which were also significantly associated with SCC survival (HRcg11637544 = 1.32, 95%CI, 1.16-1.50,P = 1.1 × 10-4;HRcg26662347 = 1.88, 95%CI, 1.37-2.60,P = 3.7 × 10-3), and correlated with corresponding gene expression (cg11637544 forKDM2A,P = 1.3 × 10-10; cg26662347 forKDM1A P = 1.5 × 10-5). In addition, by using flexible criteria for Ranger analysis followed by survival classification tree analysis, we identified four clusters for adenocarcinomas and five clusters for squamous cell carcinomas which showed a considerable difference of clinical outcomes with statistical significance.

Conclusions: These findings highlight the association between somatic DNA methylation inKDMgenes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets.

Details

Authors
  • Yongyue Wei
  • Junya Liang
  • Ruyang Zhang
  • Yichen Guo
  • Sipeng Shen
  • Li Su
  • Xihong Lin
  • Sebastian Moran
  • Åslaug Helland
  • Maria M Bjaanæs
  • Anna Karlsson
  • Maria Planck
  • Manel Esteller
  • Thomas Fleischer
  • Johan Staaf
  • Yang Zhao
  • Feng Chen
  • David C Christiani
Organisations
External organisations
  • Harvard University
  • Massachusetts General Hospital
  • Nanjing Medical University
  • Bellvitge University Hospital-IDIBELL
  • Oslo university hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • Journal Article
Original languageEnglish
Article number41
JournalClinical Epigenetics
Volume10
Publication statusPublished - 2018 Apr 2
Publication categoryResearch
Peer-reviewedYes

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