Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer

M. R. J. Kohonen-Corish*, N. D. Sigglekow, J. Susanto, P. H. Chapuis, E. L. Bokey, O. F. Dent, C. Chan, B. P. C. Lin, T. J. Seng, P. W. Laird, J. Young, B. A. Leggett, J. R. Jass, R. L. Sutherland

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

Abstract

The mutated in colorectal cancer (MCC) gene is in close linkage with the adenomatous polyposis coli (APC) gene on chromosome 5, in a region of frequent loss of heterozygosity in colorectal cancer. The role of MCC in carcinogenesis, however, has not been extensively analysed, and functional studies are emerging, which implicate it as a candidate tumor suppressor gene. The aim of this study was to examine loss of MCC expression due to promoter hypermethylation and its clinicopathologic significance in colorectal cancer. Correspondence of MCC methylation with gene silencing was demonstrated using bisulfite sequencing, reverse transcription-polymerase chain reaction and Western blotting. MCC methylation was detected in 45-52% of 187 primary colorectal cancers. There was a striking association with CDKN2A methylation (P<0.0001), the CpG island methylator phenotype (P<0.0001) and the BRAF V600E mutation (P<0.0001). MCC methylation was also more common (P=0.0084) in serrated polyps than in adenomas. In contrast, there was no association with APC methylation or KRAS mutations. This study demonstrates for the first time that MCC methylation is a frequent change during colorectal carcinogenesis. Furthermore, MCC methylation is significantly associated with a distinct spectrum of precursor lesions, which are suggested to give rise to cancers via the serrated neoplasia pathway.

Original languageEnglish
Pages (from-to)4435-4441
Number of pages7
JournalOncogene
Volume26
Issue number30
DOIs
Publication statusPublished - 28 Jun 2007
Externally publishedYes

Keywords

  • Clinicopathologic correlations
  • Mutated in colorectal cancer (MCC)
  • Promoter hypermethylation
  • Serrated polyps

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