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

Epigenetic modifications inlysine demethylases associate with survival of early-stage NSCLC.
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Wei Y, Liang J, Zhang R, Guo Y, Shen S, Su L, Lin X, Moran S, Helland Å, Bjaanæs MM, Karlsson A, Planck M, Esteller M, Fleischer T, Staaf J, Zhao Y, Chen F, Christiani DC,


Wei Y, Liang J, Zhang R, Guo Y, Shen S, Su L, Lin X, Moran S, Helland Å, Bjaanæs MM, Karlsson A, Planck M, Esteller M, Fleischer T, Staaf J, Zhao Y, Chen F, Christiani DC, (click to view)

Wei Y, Liang J, Zhang R, Guo Y, Shen S, Su L, Lin X, Moran S, Helland Å, Bjaanæs MM, Karlsson A, Planck M, Esteller M, Fleischer T, Staaf J, Zhao Y, Chen F, Christiani DC,

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Clinical epigenetics 2018 04 0210() 41 doi 10.1186/s13148-018-0474-3

Abstract
Background
lysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations ingenes 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 ingenes 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 inand cg26662347 inwere 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 ( = 1.32, 95%CI, 1.16-1.50, = 1.1 × 10; = 1.88, 95%CI, 1.37-2.60, = 3.7 × 10), and correlated with corresponding gene expression (cg11637544 for, = 1.3 × 10; cg26662347 for = 1.5 × 10). 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 ingenes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets.

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