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Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer
  1. Shuji Ogino (shuji_ogino{at}dfci.harvard.edu)
  1. Dana-Farber Cancer Institute, United States
    1. Takako Kawasaki
    1. Dana-Farber Cancer Institute, United States
      1. Gregory J Kirkner
      1. Brigham and Women's Hospital, United States
        1. Yuko Suemoto
        1. Dana-Farber Cancer Institute, United States
          1. Jeffrey A Meyerhardt
          1. Dana-Farber Cancer Institute, United States
            1. Charles S Fuchs
            1. Dana-Farber Cancer Institute, United States

              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 extensive promoter methylation (CIMP-low) has not been well-characterised. O-6-methylguanine-DNA methyltransferase (MGMT) acts to repair inappropriately methylated guanine residues in DNA. 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. Materials and methods: Utilizing MethyLight technology, we quantified DNA methylation in MGMT and 8 other markers (a CIMP-diagnostic panel, including CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) in 920 population-based colorectal cancers.

              Results: Tumours with both MGMT methylation and loss (assessed by immunohistochemistry) 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 9 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 tumours (33%=52/160, p=0.008). However, no such relationship was observed among the CIMP-high or CIMP-0 groups.

              Conclusion: Relationship between MGMT methylation/silencing and MSI-low is limited to only CIMP-low tumours, supporting that CIMP-low in colorectal cancer may be a different molecular phenotype from CIMP-high and CIMP-0. . Our data also support a molecular difference between MSI-L and MSS in colorectal cancer.

              • CIMP
              • CpG island methylator phenotype
              • MGMT
              • colon cancer
              • microsatellite instability

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