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MCC (mutated in colorectal cancers)

Written2013-09Maija Kohonen-Corish, Fahad Benthani, Laurent Pangon
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW 2010 Australia

(Note : for Links provided by Atlas : click)


Alias (NCBI)MCC1
HGNC Previous namemutated in colorectal cancers
 MCC, WNT signaling pathway regulator
LocusID (NCBI) 4163
Atlas_Id 330
Location 5q22.2  [Link to chromosome band 5q22]
Location_base_pair Starts at 113022106 and ends at 113294938 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping MCC.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
BMPR1B (4q22.3)::MCC (5q22.2)EIF4G1 (3q27.1)::MCC (5q22.2)MCC (5q22.2)::MCC (5q22.2)
MCC (5q22.2)::PSMD6 (3p14.1)REEP5 (5q22.2)::MCC (5q22.2)


Note The MCC gene was discovered in 1991 due to its linkage with the APC gene (Kinzler et al., 1991; Nishisho et al., 1991). APC was quickly recognised as a key tumour suppressor gene and MCC is now also emerging as an important gene in cancer. MCC has multiple cellular functions and is frequently altered in colorectal cancer.
Description Three isoforms of MCC have been identified; MCC-001 (17 exons), MCC-003 (19 exons) and MCC-011 (17 exons). MCC-001 and MCC-003 are known protein coding isoforms and MCC-011 is a putative protein coding isoform.
Transcription In addition to the three protein coding transcripts, there are at least six non-coding transcripts (splice variants) of varying length.


Description MCC-001, 829 aa, known protein, predicted 93 kD; observed at 105 kD.
MCC-003, 1019 aa, known protein, predicted 113 kD.
MCC-011, 766 aa, putative protein, predicted 86 kD.
Expression Limited protein expression data are available but it appears that MCC expression is variable in different tissues. MCC protein is most highly expressed in the colon, heart, lung and brain (Pangon et al., unpublished).
Localisation Cytoplasm, membrane cortex, nucleus.
Function MCC is a tumour suppressor gene in colon and liver cancer. It regulates multiple cellular processes in epithelial cells, such as proliferation (Matsumine et al., 1996), DNA damage response (Pangon et al., 2010), lamellipodia formation (Pangon et al., 2012) and cell migration (Arnaud et al., 2009). MCC can suppress Wnt and NFkB signalling pathways (Bouwmeester et al., 2004; Fukuyama et al., 2008; Sigglekow et al., 2012) but the exact mechanisms remain poorly understood. The function of MCC itself can be regulated through post-transcriptional modifications, of which site-specific serine phosphorylation has been best studied (Pangon et al., 2010; Pangon et al., 2012).


Germinal There are hundreds of SNPs in the coding region of MCC. Most are missense variants although short in-frame indels or protein-truncating mutations have also been detected. No disease associations have been described for these germline variants or mutants. However, germline retrotransposition events have been identified in the MCC locus which ablate MCC expression and are associated with virally-induced hepatocellular carcinoma (Shukla et al., 2013).
Somatic Despite its name, mutations of the MCC gene are found in only ~5% of colorectal cancers but MCC gene is silenced through promoter methylation in up to 50% of colorectal cancers (Kohonen-Corish et al., 2007; Fukuyama et al., 2008). For other cancers promoter methylation data are only available for lung cancer where MCC is not methylated (Poursoltan et al., 2012). MCC mutations have also been detected in 2-5% of other cancers, such as endometrial, melanoma, bladder urothelial, gastric, lung and prostate. Homozygous deletions have been detected in 2-4% of bladder urothelial carcinomas, ovarian serous cystadenocarcinomas, acute myeloid leukemias, prostate and gastric adenocarcinomas. MCC expression is downregulated in a subset of hepatocellular carcinomas possibly through several mechanisms, including LINE-1 insertion (Shukla et al., 2013) and targeting by oncogenic miRNA-494 (Lim et al., 2013).

Implicated in

Entity Sporadic colorectal cancer
Oncogenesis Mouse experiments have shown that MCC is a tumour suppressor gene in colorectal cancer (Starr et al., 2009). In vitro experiments indicate that loss of MCC expression can impact on multiple signalling pathways but most strikingly on the activation of β-catenin directed transcription (Fukuyama et al., 2008). Aberrant activation of Wnt signalling is widely accepted as a major event in colorectal carcinogenesis and is mostly caused by APC mutations. It has been suggested that MCC silencing is also important in activating β-catenin, particularly in the context of the 'serrated neoplasia pathway' where APC mutations are less common but MCC methylation is frequent (Kohonen-Corish et al., 2007; Fukuyama et al., 2008; Li et al., 2013). Other possible tumour promoting mechanisms of MCC silencing include impaired DNA damage response to single-strand DNA breaks (Pangon et al., 2010). Site-specific phosphorylation of MCC regulates G2/M cell cycle arrest and loss of MCC is thus expected to promote proliferation of damaged cells. MCC also regulates lamellipodia formation in epithelial cells which suggests that MCC silencing could affect epithelial restitution in the colon (Pangon et al., 2012).
Entity Hepatocellular carcinoma
Oncogenesis Loss of MCC expression in hepatocellular carcinoma is associated with aberrant activation of β-catenin (Shukla et al., 2013). MCC knockdown in vitro causes increased proliferation of hepatocellular cancer cells and is accompanied by increased G1/S transition (Lim et al., 2013).
Entity Acute myeloid leukemia
Prognosis Loss of MCC expression has been studied in relation to chemotherapy responsiveness in acute myeloid leukemia. Lack of induction of MCC expression is associated with poorer responsiveness to cytarabine (Gamazon et al., 2013).


MCC, a new interacting protein for Scrib, is required for cell migration in epithelial cells.
Arnaud C, Sebbagh M, Nola S, Audebert S, Bidaut G, Hermant A, Gayet O, Dusetti NJ, Ollendorff V, Santoni MJ, Borg JP, Lecine P.
FEBS Lett. 2009 Jul 21;583(14):2326-32. doi: 10.1016/j.febslet.2009.06.034. Epub 2009 Jun 24.
PMID 19555689
A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.
Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G.
Nat Cell Biol. 2004 Feb;6(2):97-105. Epub 2004 Jan 25.
PMID 14743216
Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses beta-catenin-dependent transcription.
Fukuyama R, Niculaita R, Ng KP, Obusez E, Sanchez J, Kalady M, Aung PP, Casey G, Sizemore N.
Oncogene. 2008 Oct 9;27(46):6044-55. doi: 10.1038/onc.2008.204. Epub 2008 Jun 30.
PMID 18591935
Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients.
Gamazon ER, Lamba JK, Pounds S, Stark AL, Wheeler HE, Cao X, Im HK, Mitra AK, Rubnitz JE, Ribeiro RC, Raimondi S, Campana D, Crews KR, Wong SS, Welsh M, Hulur I, Gorsic L, Hartford CM, Zhang W, Cox NJ, Dolan ME.
Blood. 2013 May 23;121(21):4366-76. doi: 10.1182/blood-2012-10-464149. Epub 2013 Mar 28.
PMID 23538338
Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers.
Kinzler KW, Nilbert MC, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hamilton SR, Hedge P, Markham A, et al.
Science. 1991 Mar 15;251(4999):1366-70.
PMID 1848370
Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer.
Kohonen-Corish MR, Sigglekow ND, Susanto J, Chapuis PH, Bokey EL, Dent OF, Chan C, Lin BP, Seng TJ, Laird PW, Young J, Leggett BA, Jass JR, Sutherland RL.
Oncogene. 2007 Jun 28;26(30):4435-41. Epub 2007 Jan 29.
PMID 17260021
Wnt signaling pathway is activated in right colon serrated polyps correlating to specific molecular form of beta-catenin.
Li L, Fu X, Zhang W, Xiao L, Qiu Y, Peng Y, Shi L, Chen X, Zhou X, Deng M.
Hum Pathol. 2013 Jun;44(6):1079-88. doi: 10.1016/j.humpath.2012.09.013. Epub 2013 Jan 11.
PMID 23317545
MiR-494 within an oncogenic MicroRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of MCC.
Lim L, Balakrishnan A, Huskey N, Jones KD, Jodari M, Ng R, Song G, Riordan J, Anderton B, Cheung ST, Willenbring H, Dupuy A, Chen X, Brown D, Chang AN, Goga A.
Hepatology. 2013 Aug 2. doi: 10.1002/hep.26662. [Epub ahead of print]
PMID 23913442
MCC, a cytoplasmic protein that blocks cell cycle progression from the G0/G1 to S phase.
Matsumine A, Senda T, Baeg GH, Roy BC, Nakamura Y, Noda M, Toyoshima K, Akiyama T.
J Biol Chem. 1996 Apr 26;271(17):10341-6.
PMID 8626604
Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients.
Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P.
Science. 1991 Aug 9;253(5020):665-9.
PMID 1651563
The "Mutated in Colorectal Cancer" Protein Is a Novel Target of the UV-Induced DNA Damage Checkpoint.
Pangon L, Sigglekow ND, Larance M, Al-Sohaily S, Mladenova DN, Selinger CI, Musgrove EA, Kohonen-Corish MR.
Genes Cancer. 2010 Sep;1(9):917-26. doi: 10.1177/1947601910388937.
PMID 21779472
The PDZ-binding motif of MCC is phosphorylated at position -1 and controls lamellipodia formation in colon epithelial cells.
Pangon L, Van Kralingen C, Abas M, Daly RJ, Musgrove EA, Kohonen-Corish MR.
Biochim Biophys Acta. 2012 Jun;1823(6):1058-67. doi: 10.1016/j.bbamcr.2012.03.011. Epub 2012 Mar 28.
PMID 22480440
Loss of heterozygosity of the Mutated in Colorectal Cancer gene is not associated with promoter methylation in non-small cell lung cancer.
Poursoltan P, Currey N, Pangon L, van Kralingen C, Selinger CI, Mahar A, Cooper WA, Kennedy CW, McCaughan BC, Trent R, Kohonen-Corish MR.
Lung Cancer. 2012 Aug;77(2):272-6. doi: 10.1016/j.lungcan.2012.04.001. Epub 2012 Apr 26.
PMID 22542170
Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma.
Shukla R, Upton KR, Munoz-Lopez M, Gerhardt DJ, Fisher ME, Nguyen T, Brennan PM, Baillie JK, Collino A, Ghisletti S, Sinha S, Iannelli F, Radaelli E, Dos Santos A, Rapoud D, Guettier C, Samuel D, Natoli G, Carninci P, Ciccarelli FD, Garcia-Perez JL, Faivre J, Faulkner GJ.
Cell. 2013 Mar 28;153(1):101-11. doi: 10.1016/j.cell.2013.02.032.
PMID 23540693
Mutated in colorectal cancer protein modulates the NFkB pathway.
Sigglekow ND, Pangon L, Brummer T, Molloy M, Hawkins NJ, Ward RL, Musgrove EA, Kohonen-Corish MR.
Anticancer Res. 2012 Jan;32(1):73-9.
PMID 22213290
A transposon-based genetic screen in mice identifies genes altered in colorectal cancer.
Starr TK, Allaei R, Silverstein KA, Staggs RA, Sarver AL, Bergemann TL, Gupta M, O'Sullivan MG, Matise I, Dupuy AJ, Collier LS, Powers S, Oberg AL, Asmann YW, Thibodeau SN, Tessarollo L, Copeland NG, Jenkins NA, Cormier RT, Largaespada DA.
Science. 2009 Mar 27;323(5922):1747-50. doi: 10.1126/science.1163040. Epub 2009 Feb 26.
PMID 19251594


This paper should be referenced as such :
Kohonen-Corish, M ; Benthani, F ; Pangon, L
MCC (mutated in colorectal cancers)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(4):269-271.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)MCC   6935
Entrez_Gene (NCBI)MCC    MCC regulator of WNT signaling pathway
GeneCards (Weizmann)MCC
Ensembl hg19 (Hinxton)ENSG00000171444 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000171444 [Gene_View]  ENSG00000171444 [Sequence]  chr5:113022106-113294938 [Contig_View]  MCC [Vega]
ICGC DataPortalENSG00000171444
TCGA cBioPortalMCC
Genatlas (Paris)MCC
SOURCE (Princeton)MCC
Genetics Home Reference (NIH)MCC
Genomic and cartography
GoldenPath hg38 (UCSC)MCC  -     chr5:113022106-113294938 -  5q22.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MCC  -     5q22.2   [Description]    (hg19-Feb_2009)
GoldenPathMCC - 5q22.2 [CytoView hg19]  MCC - 5q22.2 [CytoView hg38]
Genome Data Viewer NCBIMCC [Mapview hg19]  
OMIM114500   159350   
Gene and transcription
Genbank (Entrez)AK096212 AK128596 AK300259 AL359558 BC009279
RefSeq transcript (Entrez)NM_001085377 NM_002387
Consensus coding sequences : CCDS (NCBI)MCC
Gene ExpressionMCC [ NCBI-GEO ]   MCC [ EBI - ARRAY_EXPRESS ]   MCC [ SEEK ]   MCC [ MEM ]
Gene Expression Viewer (FireBrowse)MCC [ Firebrowse - Broad ]
GenevisibleExpression of MCC in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4163
GTEX Portal (Tissue expression)MCC
Human Protein AtlasENSG00000171444-MCC [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP23508   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP23508  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP23508
Domains : Interpro (EBI)USBP1-like    USH1C-bd_PDZ_domain   
Domain families : Pfam (Sanger)MCC-bdg_PDZ (PF10506)   
Domain families : Pfam (NCBI)pfam10506   
Conserved Domain (NCBI)MCC
PDB Europe6MTU    6MTV   
PDB (PDBSum)6MTU    6MTV   
PDB (IMB)6MTU    6MTV   
Structural Biology KnowledgeBase6MTU    6MTV   
SCOP (Structural Classification of Proteins)6MTU    6MTV   
CATH (Classification of proteins structures)6MTU    6MTV   
AlphaFold pdb e-kbP23508   
Human Protein Atlas [tissue]ENSG00000171444-MCC [tissue]
Protein Interaction databases
IntAct (EBI)P23508
Ontologies - Pathways
Ontology : AmiGOprotein binding  nucleus  nucleoplasm  cytoplasm  cytosol  plasma membrane  signal transduction  negative regulation of epithelial cell migration  Wnt signaling pathway  lamellipodium  cytoplasmic ribonucleoprotein granule  signaling receptor activity  establishment of protein localization  negative regulation of epithelial cell proliferation  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  
Ontology : EGO-EBIprotein binding  nucleus  nucleoplasm  cytoplasm  cytosol  plasma membrane  signal transduction  negative regulation of epithelial cell migration  Wnt signaling pathway  lamellipodium  cytoplasmic ribonucleoprotein granule  signaling receptor activity  establishment of protein localization  negative regulation of epithelial cell proliferation  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  
NDEx NetworkMCC
Atlas of Cancer Signalling NetworkMCC
Wikipedia pathwaysMCC
Orthology - Evolution
GeneTree (enSembl)ENSG00000171444
Phylogenetic Trees/Animal Genes : TreeFamMCC
Homologs : HomoloGeneMCC
Homology/Alignments : Family Browser (UCSC)MCC
Gene fusions - Rearrangements
Fusion : MitelmanBMPR1B::MCC [4q22.3/5q22.2]  
Fusion : MitelmanMCC::PSMD6 [5q22.2/3p14.1]  
Fusion : QuiverMCC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMCC [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MCC
Exome Variant ServerMCC
GNOMAD BrowserENSG00000171444
Varsome BrowserMCC
ACMGMCC variants
Genomic Variants (DGV)MCC [DGVbeta]
DECIPHERMCC [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMCC 
ICGC Data PortalMCC 
TCGA Data PortalMCC 
Broad Tumor PortalMCC
OASIS PortalMCC [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMCC  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DMCC
Mutations and Diseases : HGMDMCC
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)MCC
DoCM (Curated mutations)MCC
CIViC (Clinical Interpretations of Variants in Cancer)MCC
NCG (London)MCC
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM114500    159350   
Genetic Testing Registry MCC
NextProtP23508 [Medical]
Target ValidationMCC
Huge Navigator MCC [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDMCC
Pharm GKB GenePA30679
Clinical trialMCC
DataMed IndexMCC
PubMed61 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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