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

Kohonen‐Corish, Maija; Sigglekow, Nicholas David; Susanto, Johana M.; Chapuis, Pierre; Bokey, E. L.; Dent, Owen F.; Chan, Charles; Lin, Betty; Seng, Tzer Jing; Laird, Peter W.; Young, Joanne; Leggett, Barbara A.; Jass, J R; Sutherland, R. L.

doi:10.1038/sj.onc.1210210

Cited by 64 publications

(78 citation statements)

References 24 publications

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“…18,25 The majority (60-91%) of conventional tubular adenomas or adenocarcinomas have APC mutations, 15,16 but to our knowledge no mutational study of APC has been conducted in SSA/Ps, although methylation of APC has been reported to be more frequent in tubular adenomas (56-65%) than SSA/Ps (22-25%). 8,20 In the present work, APC was not methylated in our SSA/P series, suggesting that methylation of APC is not responsible for nuclear translocation of b-catenin. In immunohistochemical studies, strong APC expression was observed in most SSA/Ps, whereas MCC expression was reported to be frequently lost.…”

Section: Modern Pathology (2015) 28 146-158mentioning

confidence: 39%

“…21,22 MCC methylation is more common in SSA/Ps (89%) than in adenomas (35%). 20 Our study showed that MCC was methylated in 15% of SSA/Ps, and in all of SSA/Ps with high-grade dysplasia and those with submucosal carcinoma, but only 11-16% of the adenoma series. In our SSA/ P series, a fairly strong correlation was evident between nuclear b-catenin expression and methylation of AXIN2 or MCC.…”

Section: Modern Pathology (2015) 28 146-158mentioning

confidence: 51%

“…As a result, free b-catenin accumulates and translocates into the nucleus and subsequently binds to the T-cell factor/ lymphoid enhancer factor initiating transcription of target genes such as c-myc. 17 b-Catenin is also regulated by various other components such as mutated in colorectal cancer (MCC) and secreted frizzled-related proteins (SFRPs); 17 the functions of MCC or SFRPs as negative regulators of WNT/b-catenin signaling may have important implications in genesis of colorectal carcinomas [19][20][21] as well as SSA/P. 22 AXIN2 has been found to be silenced, apparently as a result of methylation of its promoter region, specifically in colorectal carcinomas with high levels of microsatellite instability.…”

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confidence: 99%

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Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum

et al. 2015

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Sessile serrated adenoma/polyp (SSA/P) is considered as an early precursor in the serrated neoplasia pathway leading to colorectal cancer development. The conventional adenoma-carcinoma sequence is associated with activation of the WNT signaling pathway, although its role in serrated lesions is still controversial. To clarify differences in WNT signaling activation in association with MLH1 methylation or BRAF/KRAS mutations between serrated and conventional routes, we performed b-catenin immunostaining, methylation-specific PCR for MLH1 and WNT signaling associated genes such as AXIN2, APC, and MCC and secreted frizzled-related proteins (SFRPs), and direct sequencing of BRAF/KRAS in 27 SSA/Ps, 14 SSA/Ps with high-grade dysplasia and 9 SSA/Ps with submucosal carcinoma, as well as 19 conventional adenomas, 26 adenomas with high-grade dysplasia and 25 adenomas with submucosal carcinoma. Nuclear b-catenin labelings were significantly lower in the serrated series than in their adenoma counterparts, and a significant increment in those labelings was found from SSA/Ps to those with high-grade dysplasia or submucosal carcinoma. The frequency of MLH1 and SFRP4 methylation was significantly higher in SSA/P series, as compared with corresponding adenoma series. AXIN2 and MCC were more frequently methylated in SSA/Ps with high-grade dysplasia and those with submucosal carcinoma than in adenoma counterparts. Stepwise increment of AXIN2 and MCC methylation was identified from SSA/Ps through those with high-grade dysplasia to those with submucosal carcinoma. A significant correlation was seen between nuclear b-catenin expression and methylation of AXIN2 or MCC in the SSA/P series. BRAF mutation was more frequent, whereas KRAS mutation was less frequent in the SSA/P series as compared with the adenoma series. There was an inverse association of BRAF mutation with AXIN2 methylation in SSA/P series. In conclusion, WNT/b-catenin signal activation mediated by the methylation of SFRP4, MCC, and AXIN2 may make different contributions to colorectal neoplasia between the serrated and conventional routes.

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Section: Modern Pathology (2015) 28 146-158mentioning

confidence: 39%

Section: Modern Pathology (2015) 28 146-158mentioning

confidence: 51%

mentioning

confidence: 99%

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Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum

et al. 2015

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“…MCC is lost by promoter methylation in CIMP þ sporadic CRC tumors and cell lines and is associated with BRAF mutation As a previous study had found a significant correlation of MCC promoter methylation to CIMP and BRAF V600E mutation (Kohonen-Corish et al, 2007), we decided to analyse MCC promoter methylation quantitatively in a separate independent cohort of 24 CIMP-positive (CIMP þ ) and 24 CIMP-negative (CIMPÀ) colorectal tumors from a consecutive series of CRC patients with known CIMP and BRAF/KRAS mutation status. MCC methylation was detected in 28 out of 48 sporadic cancer specimens (58.3%).…”

Section: Resultsmentioning

confidence: 99%

“…Most recently, promoter methylation of MCC was found to be a frequent early event in CRC. MCC promoter methylation was highly associated with a distinct subset of CRC characterized by the CpG island methylator phenotype (CIMP) and BRAF V600E mutation (Kohonen-Corish et al, 2007) which constitute the serrated CRC pathway. Serrated CRC comprises a morphologically and genetically distinct group of CRC and precursor lesions in which CRC development and progression appear driven by an alternative molecular pathway (Jass et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription

et al. 2008

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Mutated in colorectal cancer (MCC ) was originally identified as a candidate gene for familial adenomatous polyposis (FAP) but further study identified adenomatous polyposis coli (APC) as responsible for FAP and the physiologic/pathologic roles of MCC remained poorly understood. Recently, MCC promoter methylation was discovered as a frequent early event in a distinct subset of precursor lesions and colorectal cancer (CRC) associated with the serrated CRC pathway. Here we provide the first evidence of the biological significance of MCC loss in CRC and the molecular pathways involved. We show MCC expression is dramatically decreased in many CRC cell lines and the distinct subset of sporadic CRC characterized by the CpG island methylator phenotype and BRAF V600E mutation due to promoter methylation as reported previously. Importantly, we find MCC interacts with b-catenin and that reexpression of MCC in CRC cells specifically inhibits Wnt signaling, b-catenin/T-cell factor/lymphoid-enhancer factor-dependent transcription and cellular proliferation even in the presence of oncogenic mutant APC. We also show that MCC is localized in the nucleus and identify two functional nuclear localization signals. Taken together, MCC is a nuclear, b-catenininteracting protein that can act as a potential tumor suppressor in the serrated CRC pathway by inhibiting Wnt/b-catenin signal transduction.

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Mutated in colorectal cancer (Mcc), a candidate tumor suppressor, is dynamically expressed during mouse embryogenesis

et al. 2011

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Mutated in Colorectal Cancer (MCC) encodes a multiple PSD‐95/Dlg/ZO‐1 (PDZ) domain‐containing protein implicated, as its name suggests, in the pathogenesis of human colon cancer. To date, however, what role, if any, MCC plays in normal tissue homeostasis and development remains unclear. In an effort to expand our understanding of MCC function and distribution, we examined the expression of the evolutionarily conserved mouse Mcc homolog between embryonic days (E) 6.5 and 12.5 using conventional whole‐mount in situ hybridization and two independent Mcc reporter alleles. Mcc is expressed in the posterior primitive streak during gastrulation and in diverse tissues of both mesodermal and endodermal origin. In addition, Mcc transcripts localize to the posterior neural tube and identify discrete neuronal subtypes and ganglia within the developing central nervous system. Genetically, however, Mcc is entirely dispensable, as mice homozygous for the MccGt(D062B07) gene trap allele, which generates a loss‐of‐function mutation, are viable and fertile, with no ostensible phenotype. Developmental Dynamics 240:2166–2174, 2011. © 2011 Wiley‐Liss, Inc.

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

Cited by 64 publications

References 24 publications

Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum

Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum

Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription

Mutated in colorectal cancer (Mcc), a candidate tumor suppressor, is dynamically expressed during mouse embryogenesis

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