Article Text

PDF
Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer
  1. Shuji Ogino1,
  2. Takako Kawasaki2,
  3. Gregory J Kirkner3,
  4. Yuko Suemoto2,
  5. Jeffrey A Meyerhardt4,
  6. Charles S Fuchs4
  1. 1
    Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA
  2. 2
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  3. 3
    Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
  4. 4
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
  1. Dr Shuji Ogino, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 75 Francis St, BWH Pathology, Boston, MA 02115, USA; shuji_ogino{at}dfci.harvard.edu

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

Statistics from Altmetric.com

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

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.