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APC (adenomatous polyposis coli)

Written2005-03Jennifer S Tirnauer
Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, E1032, Farmington, CT 06030-3101, USA
This article is an update of :
1998-04Richard Hamelin
INSERM U434, CEPH, 27, rue Juliette Dodu, 75010 Paris, France

(Note : for Links provided by Atlas : click)

Identity

HGNC (Hugo) APC
HGNC Alias symbDP2
DP3
DP2.5
PPP1R46
HGNC Alias nameprotein phosphatase 1, regulatory subunit 46
HGNC Previous nameadenomatosis polyposis coli
 adenomatous polyposis coli
 APC, WNT signaling pathway regulator
LocusID (NCBI) 324
Atlas_Id 118
Location 5q22.2  [Link to chromosome band 5q22]
Location_base_pair Starts at 112737885 and ends at 112846239 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping APC.png]
 
  APC (5q21) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
APC (5q22.2)::ALDH1L1 (3q21.3)APC (5q22.2)::APC (5q22.2)APC (5q22.2)::KCNN2 (5q22.3)
APC (5q22.2)::KRT6A (12q13.13)APC (5q22.2)::RBMS1 (2q24.2)APC (5q22.2)::REEP2 (5q31.2)
APC (5q22.2)::SYTL4 (Xq22.1)ATP6AP2 (Xp11.4)::APC (5q22.2)PSMC2 (7q22.1)::APC (5q22.2)
RBMS1 (2q24.2)::APC (5q22.2)TPST1 (7q11.21)::APC (5q22.2)

DNA/RNA

Description 15 exons (with a particularly large 15th exon).
Transcription 9.0 kb mRNA; 8538 bp open reading frame.

Protein

Description 2843 amino acids; 310 kDa.
Function APC is a classical tumour suppressor protein. The APC gene product indirectly regulates transcription of a number of critical cell proliferation genes, through its interaction with the transcription factor beta catenin. APC binding to beta catenin leads to ubiquitin-mediated beta catenin destruction; loss of APC function increases transcription of beta catenin targets. These targets include cyclin D, C-myc, ephrins and caspases. APC also interacts with numerous actin and microtubule associated proteins. APC itself stabilizes microtubules. Homozygous APC truncation has been shown to affect chromosome attachment in cultured cells. Roles for APC in cell migration have been demonstrated in vitro and in mouse models.
Homology A second family member, APC2, is located on 19p13.3 (see non-annotated genes).

Mutations

Germinal Germline mutations of APC cause a spectrum of diseases under the broad category of familial adenomatous polyposis (FAP).
Mutations typically cluster in or just distal to the armadillo repeat region and truncate the protein near its middle. It is not known which is pathophysiologic - absence of the full-length protein or presence of the truncated version; evidence exists for both. The second hit creates another truncation or gene deletion. There is some evidence that the position of the first hit in the gene determines the pattern of the second hit.
Rare hypomorphic mutations cause attenuated polyposis.
Somatic Both copies of the APC gene are mutated in 80% of sporadic colorectal tumours.

Implicated in

Note
  
Entity Familial Adenomatous Polyposis (FAP)
Disease Autosomal dominant disease in which patients develop thousands of colonic polyps during childhood and adolescence. Many of these will progress to cancers if not removed.
FAP encompasses other disease syndromes with extra-colonic manifestations.

In Gardner Syndrome, patients may develop the following extra-intestinal manifestations:

  • Gastric and duodenal malignancies.
  • Cancer of the pancreas, biliary tree, and gallbladder.
  • Hepatoblastoma.
  • Congenital hypertrophy of the retinal pigment epithelium (CHRPE), a benign hyperpigmentation beneath the retina that is typically asymptomatic.
  • Desmoid tumors, a tumor of the connective tissue that can cause morbidity and mortality by impinging on adjacent structures.
  • Osteomas and dental abnormalities.
  • Epidermoid cysts and other skin abnormalities.

    In a subset of patients with Turcot's syndrome, intestinal polyposis due to APC mutation is associated with brain tumors, especially meduloblastoma.

  • Prognosis Without treatment, the life expectancy is in the early 40s due to colon cancer. Treatment consists of regular screening, with polypectomy of large lesions. Due to the large number of polyps, eventual complete colectomy with or without proctosigmoidectomy is needed. Regular use of the cyclooxygenase inhibitor Sulindac and possibly other member of this class of drugs reduces the number of polyps. About ten percent of patients also experience significant morbidity from desmoid tumors.
      
      
    Entity Sporadic colorectal cancer
    Disease Somatic mutation of the APC gene is found in the majority of colorectal adenocarcinomas. Sporadic colorectal cancer is the third most frequent cancer in the world.
    Prognosis The prognosis depends on the stage of the disease. Stage I lesions are usually cured by surgery. There is controversy about the use of chemotherapy in Stage II disease. In Stage III disease, chemotherapy improves the five year survival from ~50% to ~60%.
    Oncogenesis Loss of normal APC function is known to be an early event in both familial and sporadic colon cancer pathogenesis, occurring at the pre-adenoma stage. Current discussion is focused on whether loss of APC function precedes, follows, or is entwined with chromosomal instability. Later events include abnormalities of K-ras and p53.

    Generally colon cancers show either chromosomal instability (CIN), which correlates with loss of APC function, or microsatellite instability (MIN), which correlates with loss of mismatch repair function, but not both.

      

    Bibliography

    Biology of the adenomatous polyposis coli tumor suppressor.
    Goss KH, Groden J
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2000 ; 18 (9) : 1967-1979.
    PMID 10784639
     
    Identification and characterization of the familial adenomatous polyposis coli gene.
    Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M
    Cell. 1991 ; 66 (3) : 589-600.
    PMID 1651174
     
    Lessons from hereditary colorectal cancer.
    Kinzler KW, Vogelstein B
    Cell. 1996 ; 87 (2) : 159-170.
    PMID 8861899
     
    The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium.
    Nä IS
    Annual review of cell and developmental biology. 2004 ; 20 : 337-366.
    PMID 15473844
     
    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 (New York, N.Y.). 1991 ; 253 (5020) : 665-669.
    PMID 1651563
     
    APC mutations occur early during colorectal tumorigenesis.
    Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B, Kinzler KW
    Nature. 1992 ; 359 (6392) : 235-237.
    PMID 1528264
     

    Citation

    This paper should be referenced as such :
    Tirnauer, J
    APC (adenomatous polyposis coli)
    Atlas Genet Cytogenet Oncol Haematol. 2005;9(2):132-133.
    Free journal version : [ pdf ]   [ DOI ]
    History of this paper:
    Hamelin, P. APC (adenomatous polyposis coli). Atlas Genet Cytogenet Oncol Haematol. 1998;2(3):75-76.
    http://documents.irevues.inist.fr/bitstream/handle/2042/37429/04-1998-APC118.pdf


    Other Leukemias implicated (Data extracted from papers in the Atlas) [ 3 ]
      Primary mediastinal B-cell lymphoma (PMBL)
    t(3;21)(q26;q11) NRIP1::MECOM
    Therapy-Related Hematopoietic Neoplasia


    Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 5 ]
      APC-associated polyposis conditions Familial glioma Familial nervous system tumour syndromes Hereditary desmoid disease. Turcot syndrome


    External links

     

    Nomenclature
    HGNC (Hugo)APC   583
    LRG (Locus Reference Genomic)LRG_130
    Cards
    AtlasAPCID118
    Atlas Explorer : (Salamanque)APC
    Entrez_Gene (NCBI)APC    APC regulator of WNT signaling pathway
    AliasesBTPS2; DESMD; DP2; DP2.5; 
    DP3; GS; PPP1R46
    GeneCards (Weizmann)APC
    Ensembl hg19 (Hinxton)ENSG00000134982 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000134982 [Gene_View]  ENSG00000134982 [Sequence]  chr5:112737885-112846239 [Contig_View]  APC [Vega]
    ICGC DataPortalENSG00000134982
    TCGA cBioPortalAPC
    AceView (NCBI)APC
    Genatlas (Paris)APC
    SOURCE (Princeton)APC
    Genetics Home Reference (NIH)APC
    Genomic and cartography
    GoldenPath hg38 (UCSC)APC  -     chr5:112737885-112846239 +  5q22.2   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)APC  -     5q22.2   [Description]    (hg19-Feb_2009)
    GoldenPathAPC - 5q22.2 [CytoView hg19]  APC - 5q22.2 [CytoView hg38]
    ImmunoBaseENSG00000134982
    Genome Data Viewer NCBIAPC [Mapview hg19]  
    OMIM114500   114550   135290   175100   175100   611731   613659   619182   
    Gene and transcription
    Genbank (Entrez)AB210001 AF038181 AI492038 AK289567 AK294544
    RefSeq transcript (Entrez)NM_000038 NM_001127510 NM_001127511 NM_001354895 NM_001354896 NM_001354897 NM_001354898 NM_001354899 NM_001354900 NM_001354901 NM_001354902 NM_001354903 NM_001354904 NM_001354905 NM_001354906
    Consensus coding sequences : CCDS (NCBI)APC
    Gene ExpressionAPC [ NCBI-GEO ]   APC [ EBI - ARRAY_EXPRESS ]   APC [ SEEK ]   APC [ MEM ]
    Gene Expression Viewer (FireBrowse)APC [ Firebrowse - Broad ]
    GenevisibleExpression of APC in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)324
    GTEX Portal (Tissue expression)APC
    Human Protein AtlasENSG00000134982-APC [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP25054   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtP25054  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProP25054
    PhosPhoSitePlusP25054
    Domaine pattern : Prosite (Expaxy)ARM_REPEAT (PS50176)   
    Domains : Interpro (EBI)APC    APC_15aa_rpt    APC_basic_dom    APC_dom    Apc_fam    APC_N    APC_N_sf    APC_rep    APC_rpt    ARM-like    ARM-type_fold    Armadillo    EB1-bd    SAMP   
    Domain families : Pfam (Sanger)APC_15aa (PF05972)    APC_basic (PF05956)    APC_N_CC (PF16689)    APC_r (PF05923)    APC_rep (PF18797)    Arm (PF00514)    EB1_binding (PF05937)    SAMP (PF05924)   
    Domain families : Pfam (NCBI)pfam05972    pfam05956    pfam16689    pfam05923    pfam18797    pfam00514    pfam05937    pfam05924   
    Domain families : Smart (EMBL)ARM (SM00185)  
    Conserved Domain (NCBI)APC
    PDB (RSDB)1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69    4YJE    4YJL    4YK6    5B6G    5IZ6    5IZ8    5IZ9    5IZA    5Z8H   
    PDB Europe1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69    4YJE    4YJL    4YK6    5B6G    5IZ6    5IZ8    5IZ9    5IZA    5Z8H   
    PDB (PDBSum)1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69    4YJE    4YJL    4YK6    5B6G    5IZ6    5IZ8    5IZ9    5IZA    5Z8H   
    PDB (IMB)1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69    4YJE    4YJL    4YK6    5B6G    5IZ6    5IZ8    5IZ9    5IZA    5Z8H   
    Structural Biology KnowledgeBase1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69    4YJE    4YJL    4YK6    5B6G    5IZ6    5IZ8    5IZ9    5IZA    5Z8H   
    SCOP (Structural Classification of Proteins)1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69    4YJE    4YJL    4YK6    5B6G    5IZ6    5IZ8    5IZ9    5IZA    5Z8H   
    CATH (Classification of proteins structures)1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69    4YJE    4YJL    4YK6    5B6G    5IZ6    5IZ8    5IZ9    5IZA    5Z8H   
    SuperfamilyP25054
    AlphaFold pdb e-kbP25054   
    Human Protein Atlas [tissue]ENSG00000134982-APC [tissue]
    HPRD01439
    Protein Interaction databases
    DIP (DOE-UCLA)P25054
    IntAct (EBI)P25054
    Complex Portal (EBI)P25054 CPX-107 Beta-catenin destruction core complex, variant 5
    P25054 CPX-109 Beta-catenin destruction core complex, variant 1
    P25054 CPX-441 Beta-catenin destruction core complex, variant 7
    P25054 CPX-439 Beta-catenin destruction core complex, variant 3
    BioGRIDAPC
    STRING (EMBL)APC
    ZODIACAPC
    Ontologies - Pathways
    QuickGOP25054
    Ontology : AmiGOmitotic cytokinesis  kinetochore  cell fate specification  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  Golgi apparatus  centrosome  cytosol  microtubule  cytoplasmic microtubule  plasma membrane  plasma membrane  adherens junction  bicellular tight junction  cellular response to DNA damage stimulus  negative regulation of microtubule depolymerization  negative regulation of microtubule depolymerization  negative regulation of microtubule depolymerization  mitotic spindle assembly checkpoint signaling  cell adhesion  pattern specification process  nervous system development  beta-catenin binding  beta-catenin binding  beta-catenin binding  microtubule binding  microtubule binding  negative regulation of cell population proliferation  insulin receptor signaling pathway  positive regulation of cell death  Wnt signaling pathway  lateral plasma membrane  catenin complex  catenin complex  cell migration  cell migration  protein kinase regulator activity  protein kinase binding  lamellipodium  positive regulation of cell migration  beta-catenin destruction complex  beta-catenin destruction complex  positive regulation of pseudopodium assembly  ubiquitin protein ligase binding  ruffle membrane  regulation of microtubule-based process  positive regulation of apoptotic process  gamma-catenin binding  gamma-catenin binding  cadherin binding  regulation of cell differentiation  positive regulation of protein catabolic process  positive regulation of protein catabolic process  positive regulation of protein catabolic process  negative regulation of cyclin-dependent protein serine/threonine kinase activity  perinuclear region of cytoplasm  microtubule plus-end binding  regulation of attachment of spindle microtubules to kinetochore  regulation of attachment of spindle microtubules to kinetochore  protein-containing complex assembly  bicellular tight junction assembly  dynein complex binding  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  positive regulation of cold-induced thermogenesis  negative regulation of cell cycle G1/S phase transition  positive regulation of protein localization to centrosome  Wnt signalosome  negative regulation of G1/S transition of mitotic cell cycle  
    Ontology : EGO-EBImitotic cytokinesis  kinetochore  cell fate specification  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  Golgi apparatus  centrosome  cytosol  microtubule  cytoplasmic microtubule  plasma membrane  plasma membrane  adherens junction  bicellular tight junction  cellular response to DNA damage stimulus  negative regulation of microtubule depolymerization  negative regulation of microtubule depolymerization  negative regulation of microtubule depolymerization  mitotic spindle assembly checkpoint signaling  cell adhesion  pattern specification process  nervous system development  beta-catenin binding  beta-catenin binding  beta-catenin binding  microtubule binding  microtubule binding  negative regulation of cell population proliferation  insulin receptor signaling pathway  positive regulation of cell death  Wnt signaling pathway  lateral plasma membrane  catenin complex  catenin complex  cell migration  cell migration  protein kinase regulator activity  protein kinase binding  lamellipodium  positive regulation of cell migration  beta-catenin destruction complex  beta-catenin destruction complex  positive regulation of pseudopodium assembly  ubiquitin protein ligase binding  ruffle membrane  regulation of microtubule-based process  positive regulation of apoptotic process  gamma-catenin binding  gamma-catenin binding  cadherin binding  regulation of cell differentiation  positive regulation of protein catabolic process  positive regulation of protein catabolic process  positive regulation of protein catabolic process  negative regulation of cyclin-dependent protein serine/threonine kinase activity  perinuclear region of cytoplasm  microtubule plus-end binding  regulation of attachment of spindle microtubules to kinetochore  regulation of attachment of spindle microtubules to kinetochore  protein-containing complex assembly  bicellular tight junction assembly  dynein complex binding  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  positive regulation of cold-induced thermogenesis  negative regulation of cell cycle G1/S phase transition  positive regulation of protein localization to centrosome  Wnt signalosome  negative regulation of G1/S transition of mitotic cell cycle  
    Pathways : BIOCARTABIOCARTA_ALKPATHWAY    BIOCARTA_GSK3PATHWAY    BIOCARTA_PITX2PATHWAY    BIOCARTA_PS1PATHWAY    BIOCARTA_TGFBPATHWAY    BIOCARTA_WNTPATHWAY   
    Pathways : KEGGKEGG_WNT_SIGNALING    KEGG_REGULATION_OF_ACTIN_CYTOSKELETON    KEGG_PATHWAYS_IN_CANCER    KEGG_COLORECTAL_CANCER    KEGG_ENDOMETRIAL_CANCER    KEGG_BASAL_CELL_CARCINOMA   
    REACTOMEP25054 [protein]
    REACTOME PathwaysR-HSA-5689896 [pathway]   
    NDEx NetworkAPC
    Atlas of Cancer Signalling NetworkAPC
    Wikipedia pathwaysAPC
    Orthology - Evolution
    OrthoDB324
    GeneTree (enSembl)ENSG00000134982
    Phylogenetic Trees/Animal Genes : TreeFamAPC
    Homologs : HomoloGeneAPC
    Homology/Alignments : Family Browser (UCSC)APC
    Gene fusions - Rearrangements
    Fusion : MitelmanAPC::ALDH1L1 [5q22.2/3q21.3]  
    Fusion : MitelmanAPC::KRT6A [5q22.2/12q13.13]  
    Fusion : FusionHubAP3B1--APC    APC--ACTR10    APC--ALAS2    APC--ALDH1L1    APC--APC    APC--C5ORF13    APC--CAPN2    APC--CD44    APC--DPYSL3    APC--EEF1DP3   
    APC--EFNA1    APC--FAM172A    APC--KCNN2    APC--KIAA0825    APC--NREP-AS1    APC--RBMS1    APC--REEP2    APC--REEP5    APC--SLC27A6    APC--SMIM14   
    APC--SRP19    APC--SYTL4    APC--UNC50    APC--YAP1    APC2--APC    APE1--APC    ATP6AP2--APC    CDH1--APC    CTNNB1--APC    MCC--APC   
    MSS--APC    MUTYH--APC    PSMC2--APC    RASGRF2--APC    RBMS1--APC    TPST1--APC    ZNF300--APC   
    Fusion : QuiverAPC
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerAPC [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)APC
    dbVarAPC
    ClinVarAPC
    MonarchAPC
    1000_GenomesAPC 
    Exome Variant ServerAPC
    GNOMAD BrowserENSG00000134982
    Varsome BrowserAPC
    ACMGAPC variants
    VarityP25054
    Genomic Variants (DGV)APC [DGVbeta]
    DECIPHERAPC [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisAPC 
    Mutations
    ICGC Data PortalAPC 
    TCGA Data PortalAPC 
    Broad Tumor PortalAPC
    OASIS PortalAPC [ Somatic mutations - Copy number]
    Cancer Gene: CensusAPC 
    Somatic Mutations in Cancer : COSMICAPC  [overview]  [genome browser]  [tissue]  [distribution]  
    Somatic Mutations in Cancer : COSMIC3DAPC
    Mutations and Diseases : HGMDAPC
    intOGen PortalAPC
    LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
    BioMutaAPC
    DgiDB (Drug Gene Interaction Database)APC
    DoCM (Curated mutations)APC
    CIViC (Clinical Interpretations of Variants in Cancer)APC
    OncoKBAPC
    NCG (London)APC
    Cancer3DAPC
    Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM114500    114550    135290    175100    175100    611731    613659    619182   
    Orphanet19550    19893    2913    21470    8665    11544    14391   
    DisGeNETAPC
    MedgenAPC
    Genetic Testing Registry APC
    NextProtP25054 [Medical]
    GENETestsAPC
    Target ValidationAPC
    Huge Navigator APC [HugePedia]
    ClinGenAPC (curated)
    Clinical trials, drugs, therapy
    MyCancerGenomeAPC
    Protein Interactions : CTDAPC
    Pharm GKB GenePA24875
    PharosP25054
    Drug Sensitivity APC
    Clinical trialAPC
    Miscellaneous
    canSAR (ICR)APC
    HarmonizomeAPC
    ARCHS4APC
    DataMed IndexAPC
    Other databaseUMD-APC (adenomatosis polyposis coli). Curators: C. Béroud and T. Soussi
    Other databaseAPC (Broad)
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    EVEXAPC
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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