1. Isocitrate dehydrogenase 1R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype
- Author
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Vicki L. J. Whitehall, Barbara A. Leggett, Ron Buttenshaw, Grant W. Montgomery, Mark Bettington, Diane McKeone, Lisa Bowdler, Leesa F. Wockner, Troy Dumenil, and Catherine Bond
- Subjects
Male ,microsatellite ,Cancer Research ,IDH1 ,colorectal cancer ,Biology ,medicine.disease_cause ,BRAF ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Cluster Analysis ,Humans ,Epigenetics ,neoplasms ,Molecular Biology ,Aged ,030304 developmental biology ,Aged, 80 and over ,Genetics ,0303 health sciences ,Mutation ,CIMP ,CpG Island Methylator Phenotype ,Brief Report ,Microsatellite instability ,DNA Methylation ,Middle Aged ,medicine.disease ,Isocitrate Dehydrogenase ,digestive system diseases ,3. Good health ,Phenotype ,Isocitrate dehydrogenase ,CpG site ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,CpG Islands ,Female ,Microsatellite Instability ,Colorectal Neoplasms - 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.
- Published
- 2014