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Clin Epigenetics. 2018 Apr 2;10:41. doi: 10.1186/s13148-018-0474-3. eCollection 2018.

Epigenetic modifications in KDM lysine demethylases associate with survival of early-stage NSCLC.

Author information

1
1Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166 China.
2
2China International Cooperation Center (CICC) for Environment and Human Health, Nanjing Medical University, Nanjing, 211166 China.
3
3Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115 USA.
4
4Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115 USA.
5
5Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia Spain.
6
6Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
7
7Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE 22381 Lund, Sweden.
8
8Pulmonary and Critical Care Unit, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02114 USA.
#
Contributed equally

Abstract

Background:

KDM lysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations in KDM genes 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 in KDM genes 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 in KDM2A and cg26662347 in KDM1A were 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 for KDM2A, P = 1.3 × 10-10; cg26662347 for KDM1A 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 in KDM genes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets.

KEYWORDS:

DNA methylation; KDM; Lung cancer; Lysine demethylase; Survival

Conflict of interest statement

The Harvard study protocol was approved by the Institutional Review Boards at Harvard School of Public Health and MGH. The Spain study was approved by the Bellvitge Biomedical Research Institute institutional review board. The Norway project was approved by the Oslo University institutional review board and regional ethics committee (S-05307). The Sweden study was approved by the Regional Ethical Review Board in Lund, Sweden (registration nos. 2004/762 and 2008/702). All patients provided written informed consent.All participants or their surrogate care providers gave written informed consent for publication.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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