Advanced

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

Wei, Yongyue; Liang, Junya; Zhang, Ruyang; Guo, Yichen; Shen, Sipeng; Su, Li; Lin, Xihong; Moran, Sebastian; Helland, Åslaug and Bjaanæs, Maria M, et al. (2018) In Clinical Epigenetics 10.
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Journal Article
in
Clinical Epigenetics
volume
10
publisher
BioMed Central
external identifiers
  • scopus:85044829507
ISSN
1868-7075
DOI
10.1186/s13148-018-0474-3
language
English
LU publication?
yes
id
3e8f4be2-60aa-40da-9de1-b368b71a130c
date added to LUP
2018-04-09 09:20:12
date last changed
2019-09-17 04:29:27
@article{3e8f4be2-60aa-40da-9de1-b368b71a130c,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>Conclusions: These findings highlight the association between somatic DNA methylation inKDMgenes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets.</p>},
  articleno    = {41},
  author       = {Wei, Yongyue and Liang, Junya and Zhang, Ruyang and Guo, Yichen and Shen, Sipeng and Su, Li and Lin, Xihong and Moran, Sebastian and Helland, Åslaug and Bjaanæs, Maria M and Karlsson, Anna and Planck, Maria and Esteller, Manel and Fleischer, Thomas and Staaf, Johan and Zhao, Yang and Chen, Feng and Christiani, David C},
  issn         = {1868-7075},
  keyword      = {Journal Article},
  language     = {eng},
  month        = {04},
  publisher    = {BioMed Central},
  series       = {Clinical Epigenetics},
  title        = {Epigenetic modifications inlysine demethylases associate with survival of early-stage NSCLC},
  url          = {http://dx.doi.org/10.1186/s13148-018-0474-3},
  volume       = {10},
  year         = {2018},
}