Article Text
Abstract
Background: The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer. In contrast, a phenotype with less widespread promoter methylation (CIMP-low) has not been well characterised. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and silencing have been associated with G>A mutations and microsatellite instability-low (MSI-low).
Aim: To examine molecular correlates with MGMT methylation/silencing in colorectal cancer.
Methods: Utilising MethyLight technology, we quantified DNA methylation in MGMT and eight other markers (a CIMP-diagnostic panel; CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) in 920 population-based colorectal cancers.
Results: Tumours with both MGMT methylation and loss were correlated positively with MSI-low (p = 0.02), CIMP-high (⩾6/8 methylated CIMP markers, p = 0.005), CIMP-low (1/8–5/8 methylated CIMP markers, p = 0.002, compared to CIMP-0 with 0/8 methylated markers), KRAS G>A mutation (p = 0.02), and inversely with 18q loss of heterozygosity (p = 0.0002). Tumours were classified into nine MSI/CIMP subtypes. Among the CIMP-low group, tumours with both MGMT methylation and loss were far more frequent in MSI-low tumours (67%, 12/18) than MSI-high tumours (5.6%, 1/18; p = 0.0003) and microsatellite stable (MSS) tumours (33%, 52/160; p = 0.008). However, no such relationship was observed among the CIMP-high or CIMP-0 groups.
Conclusion: The relationship between MGMT methylation/silencing and MSI-low is limited to only CIMP-low tumours, supporting the suggestion that CIMP-low in colorectal cancer may be a different molecular phenotype from CIMP-high and CIMP-0. Our data support a molecular difference between MSI-low and MSS in colorectal cancer, and a possible link between CIMP-low, MSI-low, MGMT methylation/loss and KRAS mutation.
- colon cancer
- MGMT
- CpG island methylator phenotype
- CIMP
- microsatellite instability
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Footnotes
Funding: This work was supported by the US National Institute of Health (NIH) grants P01 CA87969 and P01 CA55075.
Competing interests: None.
- Abbreviations:
- CACNA1G
- calcium channel, voltage-dependent, T type alpha-1G subunit
- CDKN2A
- cyclin-dependent kinase inhibitor 2A (p16/INK4A)
- CIMP
- CpG island methylator phenotype
- CRABP1
- cellular retinoic acid binding protein 1
- DAB
- diaminobenzidine
- HNPCC
- hereditary non-polyposis colorectal cancer
- IGF2
- insulin-like growth factor 2
- LOH
- loss of heterozygosity
- MGMT
- O-6-methylguanine-DNA methyltransferase
- MSI
- microsatellite instability
- MSI-H
- microsatellite instability-high
- MSI-L
- microsatellite instability-low
- MSS
- microsatellite stable
- NCI
- National Cancer Institute
- NEUROG1
- neurogenin 1
- PMR
- percentage of methylated reference (degree of methylation)
- RUNX3
- runt-related transcription factor 3
- SOCS1
- suppressor of cytokine signaling 1
- TGFBR2
- transforming growth factor-beta receptor type 2
- WGA
- whole genome amplification