1. ¹Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
2. ²St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales, Australia
3. ³Department of Colorectal Surgery, Concord Hospital and University of Sydney, Sydney, Australia
4. ⁴Department of Anatomical Pathology, Concord Hospital and University of Sydney, Sydney, Australia
5. ⁵USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
6. ⁶Molecular Cancer Epidemiology Laboratory, QIMR, Herston, Australia
7. ⁷Conjoint Gastroenterology Laboratory, Royal Brisbane and Women's Hospital Research Foundation and Queensland Institute of Medical Research, Brisbane, Australia
8. ⁸Department of Pathology, McGill University, Montreal, Canada

Correspondence: Dr MRJ Kohonen-Corish, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria street, Darlinghurst, Sydney, New South Wales 2010, Australia. E-mail: m.corish@garvan.org.au

Received 21 July 2006; Revised 8 November 2006; Accepted 13 November 2006; Published online 29 January 2007.

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.