title: Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype.
abstract: The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features.
authors.affiliation: a Conjoint Gastroenterology Laboratory; Royal Brisbane and Women's Hospital; Clinical Research Centre and the Queensland Institute of Medical Research (QIMR) ; Brisbane , Australia.
authors.forename: V L J
authors.initials: VL
authors.lastname: Whitehall
authors.forename: T D
authors.initials: TD
authors.lastname: Dumenil
authors.forename: D M
authors.initials: DM
authors.lastname: McKeone
authors.forename: C E
authors.initials: CE
authors.lastname: Bond
authors.forename: M L
authors.initials: ML
authors.lastname: Bettington
authors.forename: R L
authors.initials: RL
authors.lastname: Buttenshaw
authors.forename: L
authors.initials: L
authors.lastname: Bowdler
authors.forename: G W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: L F
authors.initials: LF
authors.lastname: Wockner
authors.forename: B A
authors.initials: BA
authors.lastname: Leggett
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: BRAF; CIMP; CIMP, CpG Island Methylator Phenotype; IDH1; IDH1, isocitrate dehydrogenase 1; MSI, microsatellite instability; MSS, microsatellite stable; colorectal cancer; microsatellite