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.
This is a preview of subscription content, access via your institution
Access options
Similar content being viewed by others
References
Ashton-Rickardt PG, Wyllie AH, Bird CC, Dunlop MG, Steel CM, Morris RG et al. (1991). MCC, a candidate familial polyposis gene in 5q21, shows frequent allele loss in colorectal and lung cancer. Oncogene 6: 1881–1886.
Bouwmeester T, Bauch A, Ruffner H, Angrand P-O, Bergamini G, Croughton K et al. (2004). A physical and functional map of the human TNF-α/NF-κB signal-transduction pathway. Nat Cell Biol 6: 97–105.
Eads CA, Danenberg KD, Kawakami K, Saltz LB, Blake C, Shibata D et al. (2000). MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28: e32.
Eads CA, Danenberg KD, Kawakami K, Saltz LB, Danenberg PV, Laird PW . (1999). CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res 59: 2302–2306.
Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN et al. (2000). Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 60: 2368–2371.
Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H et al. (1991). Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66: 589–600.
Hawkins NJ, Ward RL . (2001). Sporadic colorectal cancers with microsatellite instability and their possible origin in HP and serrated adenomas. J Natl Cancer Inst 93: 1307–1313.
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . (1996). Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93: 9821–9826.
Ikenoue T, Hikiba Y, Kanai F, Tanaka Y, Imamura J, Imamura T et al. (2003). Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res 63: 8132–8137.
Jass JR, Iino H, Ruszkiewicz A, Painter D, Solomon MJ, Koorey DJ et al. (2000). Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum. Gut 47: 43–49.
Jass JR . (2005). Serrated adenoma of the colorectum and the DNA-methylator phenotype. Nat Clin Pract Oncol 2: 398–405.
Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD et al. (2004). BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53: 1137–1144.
Karin M, Cao Y, Greten FR, Li Z-W . (2002). NF-κB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2: 301–310.
Kinzler KW, Nilbert MC, Vogelstein B, Bryan TM, Levy DB, Smith KJ et al. (1991). Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251: 1366–1370.
Kohonen-Corish MRJ, Daniel JJ, Chan C, Lin BP, Kwun SY, Dent OF et al. (2005). Low microsatellite instability is associated with poor prognosis in stage C colon cancer. J Clin Oncol 23: 2318–2324.
Matsumine A, Senda T, Baeg GH, Roy BC, Nakamura Y, Noda M et al. (1996). MCC, a cytoplasmic protein that blocks cell cycle progression from the G0/G1 to S-phase. J Biol Chem 271: 10341–10346.
Nagasaka T, Sasamoto H, Notohara K, Cullings HM, Takeda M, Kimura K et al. (2004). Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. J Clin Oncol 22: 4584–4594.
Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A et al. (1991). Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 252: 665–669.
O'Brien MJ, Yang S, Clebanoff JL, Mulcahy E, Farraye FA, Amorosino M et al. (2004). Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype. Am J Surg Pathol 28: 423–434.
Rashid A, Shen L, Morris JS, Issa JP, Hamilton SR . (2001). CpG island methylation in colorectal adenomas. Am J Pathol 159: 1129–1135.
Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA et al. (2005a). Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 129: 837–845.
Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA et al. (2005b). Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 65: 6063–6070.
Senda T, Matsumine A, Yanai H, Akiyama T . (1999). Localization of MCC (mutated in colorectal cancer) in various tissues of mice and its involvement in cell differentiation. J Histochem Cytochem 47: 1149–1157.
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP . (1999). CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96: 8681–8686.
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M et al. (1988). Genetic alterations during colorectal-tumor development. New Engl J Med 319: 525–532.
Ward RL, Cheong K, Ku SL, Meagher A, O'Connor T, Hawkins NJ . (2003). Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol 21: 3729–3736.
Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA et al. (2006). CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38: 787–793.
Wynter CVA, Walsh MD, Higuchi T, Leggett BA, Young J, Jass JR . (2004). Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer. Gut 53: 573–580.
Acknowledgements
We thank the Cancer Institute NSW, the Australian Cancer Research Foundation and the Strathfield Private Hospital for financial support and Francis Lam for providing the frozen tumor specimens. Jawad Saab, Joseph Daniel, Nicola Currey, Ron Buttenshaw, Daniel Buchanan, Hoey Koh and Lisa Simms provided expert technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kohonen-Corish, M., Sigglekow, N., Susanto, J. et al. Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer. Oncogene 26, 4435–4441 (2007). https://doi.org/10.1038/sj.onc.1210210
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210210
Keywords
This article is cited by
-
The role of APC in WNT pathway activation in serrated neoplasia
Modern Pathology (2018)
-
‘MCC’ protein interacts with E-cadherin and β-catenin strengthening cell–cell adhesion of HCT116 colon cancer cells
Oncogene (2018)
-
Allele-specific expression of mutated in colorectal cancer (MCC) gene and alternative susceptibility to colorectal cancer in schizophrenia
Scientific Reports (2016)
-
Identification of subgroup-specific miRNA patterns by epigenetic profiling of sporadic and Lynch syndrome-associated colorectal and endometrial carcinoma
Clinical Epigenetics (2015)
-
Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum
Modern Pathology (2015)