title: An epigenetic biomarker panel for glioblastoma multiforme personalized medicine through DNA methylation analysis of human embryonic stem cell-like signature.
abstract: Alterations of DNA methylation occur during the course of both stem cell development and tumorigenesis. We present a novel strategy that can be used to stratify glioblastoma multiforme (GBM) patients through the epigenetic states of genes associated with human embryonic stem cell (hESC) identity in order to 1) assess linkages between the methylation signatures of these stem cell genes and survival of GBM patients, and 2) delineate putative mechanisms leading to poor prognosis in some patient subgroups. A DNA methylation signature was established for stratifying GBM patients into several hESC methylator subgroups. The hESC methylator-negative phenotype has demonstrated poor survival and upregulation of glioma stem cell (GSC) markers, and is enriched in one of the previously defined transcriptomic phenotypes-the mesenchymal phenotype. We further identified a refined signature of 36 genes as the gene panel, including SOX2, POU3F2, FGFR2, GAP43, NTRK2, NTRK3, and NKX2-2, which are highly enriched in the nervous system. Both signatures outperformed the O6-methylguanine-DNA methyltransferase (MGMT) methylation test in predicting patient's outcome. These findings were also validated through an independent dataset of patients. Furthermore, through statistical analyses, both signatures were examined significantly. Hypomethylation of hESC-associated genes predicted poorer clinical outcome in GBM, supporting the idea that epigenetic activation of stem cell genes contributes to GBM aggression. The gene panel presented herein may be developed into clinical assays for patient stratification and future personalized medicine interventions.
authors.affiliation: 1 Department of Computer Science and Information Engineering, National Cheng Kung University , Tainan City, Taiwan .
authors.forename: Jung-Hsien
authors.initials: JH
authors.lastname: Chiang
authors.forename: Wan-Shu
authors.initials: WS
authors.lastname: Cheng
authors.forename: Leroy
authors.initials: L
authors.lastname: Hood
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tian
mesh_terms: D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000502:physiology; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D005909:Glioblastoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006801:Humans; D053208:Kaplan-Meier Estimate; D014411:Neoplastic Stem Cells / Q000502:physiology; D009687:Nuclear Proteins; D057285:Precision Medicine; D011379:Prognosis; D012372:ROC Curve; D014157:Transcription Factors
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors