title: DNA hypermethylation profiles associated with glioma subtypes and EZH2 and IGFBP2 mRNA expression.
abstract: We explored the associations of aberrant DNA methylation patterns in 12 candidate genes with adult glioma subtype, patient survival, and gene expression of enhancer of zeste human homolog 2 (EZH2) and insulin-like growth factor-binding protein 2 (IGFBP2). We analyzed 154 primary glioma tumors (37 astrocytoma II and III, 52 primary glioblastoma multiforme (GBM), 11 secondary GBM, 54 oligodendroglioma/oligoastrocytoma II and III) and 13 nonmalignant brain tissues for aberrant methylation with quantitative methylation-specific PCR (qMS-PCR) and for EZH2 and IGFBP2 expression with quantitative reverse transcription PCR (qRT-PCR). Global methylation was assessed by measuring long interspersed nuclear element-1 (LINE1) methylation. Unsupervised clustering analyses yielded 3 methylation patterns (classes). Class 1 (MGMT, PTEN, RASSF1A, TMS1, ZNF342, EMP3, SOCS1, RFX1) was highly methylated in 82% (75/91) of lower-grade astrocytic and oligodendroglial tumors, 73% (8/11) of secondary GBMs, and 12% (6/52) of primary GBMs. The primary GBMs in this class were early onset (median age 37 years). Class 2 (HOXA9 and SLIT2) was highly methylated in 37% (19/52) of primary GBMs. None of the 10 genes for class 3 that were differentially methylated in classes 1 and 2 were hypermethylated in 92% (12/13) of nonmalignant brain tissues and 52% (27/52) of primary GBMs. Class 1 tumors had elevated EZH2 expression but not elevated IGFBP2; class 2 tumors had both high IGFBP2 and high EZH2 expressions. The gene-specific hypermethylation class correlated with higher levels of global LINE1 methylation and longer patient survival times. These findings indicate a generalized hypermethylation phenotype in glioma linked to improved survival and low IGFBP2. DNA methylation markers are useful in characterizing distinct glioma subtypes and may hold promise for clinical applications.
authors.affiliation: Department of Neurological Surgery, University of California-San Francisco, Helen Diller Family Cancer Center, 1450 3rd Street, San Francisco, CA 94158, USA.
authors.forename: Shichun
authors.initials: S
authors.lastname: Zheng
authors.forename: E Andres
authors.initials: EA
authors.lastname: Houseman
authors.forename: Zachary
authors.initials: Z
authors.lastname: Morrison
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Patoka
authors.forename: Christian
authors.initials: C
authors.lastname: Ramos
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
authors.forename: Sean
authors.initials: S
authors.lastname: McBride
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Scott R
authors.initials: SR
authors.lastname: Vandenberg
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
mesh_terms: D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000145:classification / Q000235:genetics*; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics*; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D008875:Middle Aged; D063151:Polycomb Repressive Complex 2; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C512478:EGFR protein, human; D066246:ErbB Receptors