title: Tumor-suppressive miR148a is silenced by CpG island hypermethylation in IDH1-mutant gliomas.
abstract: OBJECTIVE
  IDH1/2-mutant gliomas harbor a distinct glioma-CpG island methylation phenotype (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor-suppressive genes. The potential role of tumor-suppressive microRNAs (miRNA; miR) in this process is not understood.
  
  
  METHODS
  To identify potential tumor-suppressive miRNA hypermethylated in glioma, the methylation profiles of IDH1/2(WT) gliomas (n = 11) and IDH1(MUT) glioma (n = 20) were compared by using massively parallel reduced representation bisulfite sequencing (RRBS). The methylation status of selected miRNA was validated by using targeted bisulfite sequencing (BiSEQ) in a large cohort of glioma tissue samples including 219 IDH1(WT) and 72 IDH1/2(MUT) samples. The expression of selected miRNAs was determined by using the TaqMan qPCR. Functional analyses of miR148a were conducted and target genes were identified.
  
  
  RESULTS
  We identify miR148a as a novel, G-CIMP-associated miRNA whose methylation is tightly correlated with IDH1 mutation and associated with improved survival in patients with malignant glioma. We confirm that downregulation of miR148a can occur via DNA methylation. We demonstrate that IDH1 mutation provides a mechanism of miR148a methylation and downregulation, and that restoration of miR148a reduced tumorigenic properties of glioma cells, possibly by targeting DNMT1.
  
  
  CONCLUSIONS
  We identify miR148a as a novel G-CIMP-associated miRNA, and provide results suggesting that miR148a restoration may have therapeutic implications.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Sichen
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Reshmi
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Chou
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Tie
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Reema R
authors.initials: RR
authors.lastname: Mody
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Lou
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Weidong
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pathology & Lab Med-Clinical Labs, UCLA Health System, University of California Los Angeles, Los Angeles, California.
authors.forename: Jean
authors.initials: J
authors.lastname: Reiss
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Horacio
authors.initials: H
authors.lastname: Soto
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Prins
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.affiliation: Laboratory of Molecular Pathology, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Phioanh L
authors.initials: PL
authors.lastname: Nghiemphu
authors.affiliation: Department of Pathology & Lab Med-Clinical Labs, UCLA Health System, University of California Los Angeles, Los Angeles, California.
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. albertlai@mednet.ucla.edu.
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D064593:Heterografts; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D011379:Prognosis; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C550570:MIRN148 microRNA, human; D035683:MicroRNAs; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human