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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)

Identity

Other aliasMCC1
HGNC (Hugo) MCC
LocusID (NCBI) 4163
Atlas_Id 330
Location 5q22.2  [Link to chromosome band 5q22]
Location_base_pair Starts at 113022099 and ends at 113488830 bp from pter ( according to hg19-Feb_2009)  [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)

DNA/RNA

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.

Protein

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 MCC protein is most highly expressed in the colon, heart, lung and brain (Pangon et al., unpublished).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).

Mutations

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

Note
  
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).
  

Bibliography

MCC, a new interacting protein for Scrib, is required for cell migration in epithelial cells.
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A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.
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Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses beta-catenin-dependent transcription.
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Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients.
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PMID 23538338
 
Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers.
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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.
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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.
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PMID 8626604
 
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The "Mutated in Colorectal Cancer" Protein Is a Novel Target of the UV-Induced DNA Damage Checkpoint.
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The PDZ-binding motif of MCC is phosphorylated at position -1 and controls lamellipodia formation in colon epithelial cells.
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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.
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Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma.
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Mutated in colorectal cancer protein modulates the NFkB pathway.
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Citation

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 ]
On line version : http://AtlasGeneticsOncology.org/Genes/MCCID330ch5q22.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Testis: Germ cell tumors
Squamous cell cancer


External links

Nomenclature
HGNC (Hugo)MCC   6935
Cards
AtlasMCCID330ch5q22
Entrez_Gene (NCBI)MCC  4163  mutated in colorectal cancers
AliasesMCC1
GeneCards (Weizmann)MCC
Ensembl hg19 (Hinxton)ENSG00000171444 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000171444 [Gene_View]  chr5:113022099-113488830 [Contig_View]  MCC [Vega]
ICGC DataPortalENSG00000171444
TCGA cBioPortalMCC
AceView (NCBI)MCC
Genatlas (Paris)MCC
WikiGenes4163
SOURCE (Princeton)MCC
Genetics Home Reference (NIH)MCC
Genomic and cartography
GoldenPath hg38 (UCSC)MCC  -     chr5:113022099-113488830 -  5q22.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MCC  -     5q22.2   [Description]    (hg19-Feb_2009)
EnsemblMCC - 5q22.2 [CytoView hg19]  MCC - 5q22.2 [CytoView hg38]
Mapping of homologs : NCBIMCC [Mapview hg19]  MCC [Mapview hg38]
OMIM159350   
Gene and transcription
Genbank (Entrez)AK096212 AK128596 AK300259 AL359558 AM393612
RefSeq transcript (Entrez)NM_001085377 NM_002387
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MCC
Cluster EST : UnigeneHs.593171 [ NCBI ]
CGAP (NCI)Hs.593171
Alternative Splicing GalleryENSG00000171444
Gene ExpressionMCC [ NCBI-GEO ]   MCC [ EBI - ARRAY_EXPRESS ]   MCC [ SEEK ]   MCC [ MEM ]
Gene Expression Viewer (FireBrowse)MCC [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression 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
Splice isoforms : SwissVarP23508
PhosPhoSitePlusP23508
Domains : Interpro (EBI)USH1C-bd_PDZ_domain   
Domain families : Pfam (Sanger)MCC-bdg_PDZ (PF10506)   
Domain families : Pfam (NCBI)pfam10506   
Conserved Domain (NCBI)MCC
DMDM Disease mutations4163
Blocks (Seattle)MCC
SuperfamilyP23508
Human Protein Atlas [tissue]ENSG00000171444-MCC [tissue]
Peptide AtlasP23508
HPRD01157
IPIIPI00011957   IPI00443415   IPI00902750   IPI00968083   
Protein Interaction databases
DIP (DOE-UCLA)P23508
IntAct (EBI)P23508
FunCoupENSG00000171444
BioGRIDMCC
STRING (EMBL)MCC
ZODIACMCC
Ontologies - Pathways
QuickGOP23508
Ontology : AmiGOreceptor activity  protein binding  nucleus  nucleoplasm  cytoplasm  cytosol  plasma membrane  signal transduction  negative regulation of epithelial cell migration  Wnt signaling pathway  lamellipodium  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-EBIreceptor activity  protein binding  nucleus  nucleoplasm  cytoplasm  cytosol  plasma membrane  signal transduction  negative regulation of epithelial cell migration  Wnt signaling pathway  lamellipodium  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
OrthoDB4163
GeneTree (enSembl)ENSG00000171444
Phylogenetic Trees/Animal Genes : TreeFamMCC
HOVERGENP23508
HOGENOMP23508
Homologs : HomoloGeneMCC
Homology/Alignments : Family Browser (UCSC)MCC
Gene fusions - Rearrangements
Fusion : MitelmanBMPR1B/MCC [4q22.3/5q22.2]  [t(4;5)(q22;q22)]  
Fusion : MitelmanMCC/PSMD6 [5q22.2/3p14.1]  [t(3;5)(p14;q22)]  
Fusion: TCGA_MDACCBMPR1B 4q22.3 MCC 5q22.2 BRCA
Fusion: TCGA_MDACCMCC 5q22.2 PSMD6 3p14.1 KIRC
Tumor Fusion PortalMCC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMCC [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MCC
dbVarMCC
ClinVarMCC
1000_GenomesMCC 
Exome Variant ServerMCC
ExAC (Exome Aggregation Consortium)ENSG00000171444
GNOMAD BrowserENSG00000171444
Genetic variants : HAPMAP4163
Genomic Variants (DGV)MCC [DGVbeta]
DECIPHERMCC [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMCC 
Mutations
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]  
Mutations and Diseases : HGMDMCC
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MCC
DgiDB (Drug Gene Interaction Database)MCC
DoCM (Curated mutations)MCC (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MCC (select a term)
intoGenMCC
NCG5 (London)MCC
Cancer3DMCC(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM159350   
Orphanet
DisGeNETMCC
MedgenMCC
Genetic Testing Registry MCC
NextProtP23508 [Medical]
TSGene4163
GENETestsMCC
Target ValidationMCC
Huge Navigator MCC [HugePedia]
snp3D : Map Gene to Disease4163
BioCentury BCIQMCC
ClinGenMCC
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4163
Chemical/Pharm GKB GenePA30679
Clinical trialMCC
Miscellaneous
canSAR (ICR)MCC (select the gene name)
Probes
Litterature
PubMed42 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMCC
EVEXMCC
GoPubMedMCC
iHOPMCC
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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