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 | Whitehall, V. L. J.; Dumenil, Troy D.; McKeone, D.; Bond, C. E.; Bettington, Mark; Buttenshaw, R. L.; Bowdler, L.; Montgomery, G. W.; Wockner, L. F.; Leggett, B. |
|---|---|
| Journal | Epigenetics : official journal of the DNA Methylation Society |
| Pages | 1454-60 |
| Volume | 9 |
| Date | 1/11/2014 |
| Grant ID | 442965, 1050455 |
| Funding Body | NHMRC |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.4161/15592294.2014.971624 |
| Download Article |