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APC (adenomatous polyposis coli)

Identity

HGNC (Hugo) APC
LocusID (NCBI) 324
Location 5q22.2
Location_base_pair Starts at 112073556 and ends at 112181936 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  APC (5q21) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

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

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.

      

    External links

    Nomenclature
    HGNC (Hugo)APC   583
    Cards
    AtlasAPC118
    Entrez_Gene (NCBI)APC  324  adenomatous polyposis coli
    GeneCards (Weizmann)APC
    Ensembl (Hinxton)ENSG00000134982 [Gene_View]  chr5:112073556-112181936 [Contig_View]  APC [Vega]
    AceView (NCBI)APC
    Genatlas (Paris)APC
    WikiGenes324
    SOURCE (Princeton)NM_000038 NM_001127510 NM_001127511
    Genomic and cartography
    GoldenPath (UCSC)APC  -  5q22.2   chr5:112073556-112181936 +  5q21-q22   [Description]    (hg19-Feb_2009)
    EnsemblAPC - 5q21-q22 [CytoView]
    Mapping of homologs : NCBIAPC [Mapview]
    OMIM114500   114550   135290   137215   155255   175100   276300   611731   613659   
    Gene and transcription
    Genbank (Entrez)AB210001 AF038181 AI492038 AK289567 AK294544
    RefSeq transcript (Entrez)NM_000038 NM_001127510 NM_001127511
    RefSeq genomic (Entrez)AC_000137 NC_000005 NC_018916 NG_008481 NT_034772 NW_001838952 NW_004929323
    Consensus coding sequences : CCDS (NCBI)APC
    Cluster EST : UnigeneHs.158932 [ NCBI ]
    CGAP (NCI)Hs.158932
    Alternative Splicing : Fast-db (Paris)GSHG0024148
    Alternative Splicing GalleryENSG00000134982
    Gene ExpressionAPC [ NCBI-GEO ]     APC [ SEEK ]   APC [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP25054 (Uniprot)
    NextProtP25054  [Medical]
    With graphics : InterProP25054
    Splice isoforms : SwissVarP25054 (Swissvar)
    Domaine pattern : Prosite (Expaxy)ARM_REPEAT (PS50176)   
    Domains : Interpro (EBI)APC    APC_15aa_rpt    APC_basic_dom    APC_Cys-rich_rpt    APC_dom    Apc_fam    ARM-like    ARM-type_fold    Armadillo    EB1-bd    SAMP   
    Related proteins : CluSTrP25054
    Domain families : Pfam (Sanger)APC_15aa (PF05972)    APC_basic (PF05956)    APC_crr (PF05923)    Arm (PF00514)    EB1_binding (PF05937)    SAMP (PF05924)    Suppressor_APC (PF11414)   
    Domain families : Pfam (NCBI)pfam05972    pfam05956    pfam05923    pfam00514    pfam05937    pfam05924    pfam11414   
    Domain families : Smart (EMBL)ARM (SM00185)  
    DMDM Disease mutations324
    Blocks (Seattle)P25054
    PDB (SRS)1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69   
    PDB (PDBSum)1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69   
    PDB (IMB)1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69   
    PDB (RSDB)1DEB    1EMU    1JPP    1M5I    1T08    1TH1    1V18    2RQU    3AU3    3NMW    3NMX    3NMZ    3QHE    3RL7    3RL8    3T7U    4G69   
    Human Protein AtlasENSG00000134982
    Peptide AtlasP25054
    HPRD01439
    IPIIPI00012391   IPI00215877   IPI00974301   IPI00930146   IPI00967278   IPI00979931   IPI00967116   IPI00964920   
    Protein Interaction databases
    DIP (DOE-UCLA)P25054
    IntAct (EBI)P25054
    FunCoupENSG00000134982
    BioGRIDAPC
    InParanoidP25054
    Interologous Interaction database P25054
    IntegromeDBAPC
    STRING (EMBL)APC
    Ontologies - Pathways
    Ontology : AmiGOmitotic cytokinesis  kinetochore  kidney development  hair follicle development  protein binding  nucleus  cytoplasm  centrosome  cytosol  cytoplasmic microtubule  plasma membrane  plasma membrane  cell-cell adherens junction  tight junction  protein complex assembly  apoptotic process  cellular component disassembly involved in execution phase of apoptosis  cellular response to DNA damage stimulus  negative regulation of microtubule depolymerization  negative regulation of microtubule depolymerization  cell cycle arrest  metaphase/anaphase transition of mitotic cell cycle  mitotic spindle assembly checkpoint  cell adhesion  axonogenesis  beta-catenin binding  microtubule binding  negative regulation of cell proliferation  axis specification  anterior/posterior pattern specification  dorsal/ventral pattern formation  proximal/distal pattern formation  lateral plasma membrane  cell migration  protein kinase regulator activity  protein kinase binding  lamellipodium  positive regulation of cell migration  positive regulation of epithelial cell differentiation  beta-catenin destruction complex  positive regulation of microtubule polymerization  cytoplasmic microtubule organization  positive regulation of pseudopodium assembly  ruffle membrane  regulation of microtubule-based process  T cell differentiation in thymus  somatic stem cell maintenance  microtubule plus-end  negative regulation of odontogenesis  positive regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of MAPK cascade  axonal growth cone  gamma-catenin binding  cadherin binding  regulation of osteoblast differentiation  regulation of osteoclast differentiation  positive regulation of protein catabolic process  positive regulation of protein catabolic process  negative regulation of cyclin-dependent protein serine/threonine kinase activity  positive regulation of cell adhesion  muscle cell cellular homeostasis  thymus development  microtubule plus-end binding  regulation of nitrogen compound metabolic process  chromosome organization  positive regulation of cell division  regulation of attachment of spindle microtubules to kinetochore  regulation of attachment of spindle microtubules to kinetochore  retina development in camera-type eye  canonical Wnt receptor signaling pathway  canonical Wnt receptor signaling pathway  negative regulation of epithelial cell proliferation involved in prostate gland development  tight junction assembly  negative regulation of canonical Wnt receptor signaling pathway  
    Ontology : EGO-EBImitotic cytokinesis  kinetochore  kidney development  hair follicle development  protein binding  nucleus  cytoplasm  centrosome  cytosol  cytoplasmic microtubule  plasma membrane  plasma membrane  cell-cell adherens junction  tight junction  protein complex assembly  apoptotic process  cellular component disassembly involved in execution phase of apoptosis  cellular response to DNA damage stimulus  negative regulation of microtubule depolymerization  negative regulation of microtubule depolymerization  cell cycle arrest  metaphase/anaphase transition of mitotic cell cycle  mitotic spindle assembly checkpoint  cell adhesion  axonogenesis  beta-catenin binding  microtubule binding  negative regulation of cell proliferation  axis specification  anterior/posterior pattern specification  dorsal/ventral pattern formation  proximal/distal pattern formation  lateral plasma membrane  cell migration  protein kinase regulator activity  protein kinase binding  lamellipodium  positive regulation of cell migration  positive regulation of epithelial cell differentiation  beta-catenin destruction complex  positive regulation of microtubule polymerization  cytoplasmic microtubule organization  positive regulation of pseudopodium assembly  ruffle membrane  regulation of microtubule-based process  T cell differentiation in thymus  somatic stem cell maintenance  microtubule plus-end  negative regulation of odontogenesis  positive regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of MAPK cascade  axonal growth cone  gamma-catenin binding  cadherin binding  regulation of osteoblast differentiation  regulation of osteoclast differentiation  positive regulation of protein catabolic process  positive regulation of protein catabolic process  negative regulation of cyclin-dependent protein serine/threonine kinase activity  positive regulation of cell adhesion  muscle cell cellular homeostasis  thymus development  microtubule plus-end binding  regulation of nitrogen compound metabolic process  chromosome organization  positive regulation of cell division  regulation of attachment of spindle microtubules to kinetochore  regulation of attachment of spindle microtubules to kinetochore  retina development in camera-type eye  canonical Wnt receptor signaling pathway  canonical Wnt receptor signaling pathway  negative regulation of epithelial cell proliferation involved in prostate gland development  tight junction assembly  negative regulation of canonical Wnt receptor signaling pathway  
    Pathways : BIOCARTATGF beta signaling pathway [Genes]    Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages [Genes]    Presenilin action in Notch and Wnt signaling [Genes]    ALK in cardiac myocytes [Genes]    Multi-step Regulation of Transcription by Pitx2 [Genes]    WNT Signaling Pathway [Genes]   
    Pathways : KEGGWnt signaling pathway    Hippo signaling pathway    Regulation of actin cytoskeleton    HTLV-I infection    Pathways in cancer    MicroRNAs in cancer    Colorectal cancer    Endometrial cancer    Basal cell carcinoma   
    REACTOMEAPC
    Protein Interaction DatabaseAPC
    Wikipedia pathwaysAPC
    Gene fusion - rearrangments
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)APC
    SNP (GeneSNP Utah)APC
    SNP : HGBaseAPC
    Genetic variants : HAPMAPAPC
    1000_GenomesAPC 
    ICGC programENSG00000134982 
    Cancer Gene: CensusAPC 
    Somatic Mutations in Cancer : COSMICAPC 
    CONAN: Copy Number AnalysisAPC 
    Mutations and Diseases : HGMDAPC
    OMIM114500    114550    135290    137215    155255    175100    276300    611731    613659   
    GENETestsAPC
    Disease Genetic AssociationAPC
    Huge Navigator APC [HugePedia]  APC [HugeCancerGEM]
    Genomic VariantsAPC  APC [DGVbeta]
    Exome VariantAPC
    dbVarAPC
    ClinVarAPC
    snp3D : Map Gene to Disease324
    General knowledge
    Homologs : HomoloGeneAPC
    Homology/Alignments : Family Browser (UCSC)APC
    Phylogenetic Trees/Animal Genes : TreeFamAPC
    Chemical/Protein Interactions : CTD324
    Chemical/Pharm GKB GenePA24875
    Drug Sensitivity APC
    Clinical trialAPC
    Cancer Resource (Charite)ENSG00000134982
    Other databases
    Probes
    ProbeCancer Cytogenetics (Bari)
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    CoreMineAPC
    iHOPAPC

    Bibliography

    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
     
    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
     
    Lessons from hereditary colorectal cancer.
    Kinzler KW, Vogelstein B
    Cell. 1996 ; 87 (2) : 159-170.
    PMID 8861899
     
    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
     
    The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium.
    Nˆ§thke IS
    Annual review of cell and developmental biology. 2004 ; 20 : 337-366.
    PMID 15473844
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written04-1998Richard Hamelin
    INSERM U434, CEPH, 27, rue Juliette Dodu, 75010 Paris, France
    Updated03-2005Jennifer Tirnauer

    Citation

    This paper should be referenced as such :
    Hamelin P . APC (adenomatous polyposis coli). Atlas Genet Cytogenet Oncol Haematol. April 1998 .
    Tirnauer J . APC (adenomatous polyposis coli). Atlas Genet Cytogenet Oncol Haematol. March 2005 .
    URL : http://AtlasGeneticsOncology.org/Genes/APC118.html

    The various updated versions of this paper are referenced and archived by INIST as such :
    http://documents.irevues.inist.fr/bitstream/2042/37429/1/04-1998-APC118.pdf   [ Bibliographic record ]
    http://documents.irevues.inist.fr/bitstream/2042/38183/1/03-2005-APC118.pdf   [ Bibliographic record ]

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    indexed on : Mon Mar 31 08:59:51 CEST 2014

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