Journal
EPIGENETICS
Volume 9, Issue 11, Pages 1454-1460Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/15592294.2014.971624
Keywords
BRAF; CIMP; colorectal cancer; IDH1; microsatellite; CIMP; CpG Island Methylator Phenotype; MSI; microsatellite instability; MSS; microsatellite stable; IDH1; isocitrate dehydrogenase 1
Funding
- National Health and Medical Research Council [442965, 1050455]
- Cancer Council Queensland [1025268]
- Pathology Queensland, Clinical and Statewide Services, Queensland, Australia
- Australian Postgraduate Award
- Cancer Council Queensland Postgraduate Award
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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.
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