APC (adenomatous polyposis coli)

2005-03-01   Jennifer S Tirnauer 

Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, E1032, Farmington, CT 06030-3101, USA

Identity

HGNC
LOCATION
5q22.2
IMAGE
Atlas Image
LEGEND
APC (5q21) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
LOCUSID
ALIAS
BTPS2,DESMD,DP2,DP2.5,DP3,GS,PPP1R46
FUSION GENES

DNA/RNA

Description

15 exons (with a particularly large 15th exon).

Transcription

9.0 kb mRNA; 8538 bp open reading frame.

Proteins

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 name
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:

  • Osteomas and dental abnormalities.
  • 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.
  • Epidermoid cysts and other skin abnormalities.

    In a subset of patients with Turcots 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 name
    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

    Pubmed IDLast YearTitleAuthors
    107846392000Biology of the adenomatous polyposis coli tumor suppressor.Goss KH et al
    16511741991Identification and characterization of the familial adenomatous polyposis coli gene.Groden J et al
    88618991996Lessons from hereditary colorectal cancer.Kinzler KW et al
    154738442004The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium.Näthke IS et al
    16515631991Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients.Nishisho I et al
    15282641992APC mutations occur early during colorectal tumorigenesis.Powell SM et al

    Other Information

    Locus ID:

    NCBI: 324
    MIM: 611731
    HGNC: 583
    Ensembl: ENSG00000134982

    Variants:

    dbSNP: 324
    ClinVar: 324
    TCGA: ENSG00000134982
    COSMIC: APC

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000134982ENST00000257430P25054
    ENSG00000134982ENST00000502371A0A087X2F3
    ENSG00000134982ENST00000504915R4GMU6
    ENSG00000134982ENST00000505350A0A087WYF3
    ENSG00000134982ENST00000507379A0A2Q2SV78
    ENSG00000134982ENST00000508376P25054
    ENSG00000134982ENST00000508624E7EMH9
    ENSG00000134982ENST00000509732D6RFL6
    ENSG00000134982ENST00000512211E9PFT7

    Expression (GTEx)

    0
    5
    10
    15
    20
    25
    30
    35
    40

    Pathways

    PathwaySourceExternal ID
    Wnt signaling pathwayKEGGko04310
    Regulation of actin cytoskeletonKEGGko04810
    Colorectal cancerKEGGko05210
    Endometrial cancerKEGGko05213
    Basal cell carcinomaKEGGko05217
    Wnt signaling pathwayKEGGhsa04310
    Regulation of actin cytoskeletonKEGGhsa04810
    Pathways in cancerKEGGhsa05200
    Colorectal cancerKEGGhsa05210
    Endometrial cancerKEGGhsa05213
    Basal cell carcinomaKEGGhsa05217
    HTLV-I infectionKEGGko05166
    HTLV-I infectionKEGGhsa05166
    Hippo signaling pathwayKEGGhsa04390
    Hippo signaling pathwayKEGGko04390
    MicroRNAs in cancerKEGGhsa05206
    MicroRNAs in cancerKEGGko05206
    Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
    Signaling pathways regulating pluripotency of stem cellsKEGGko04550
    Metabolism of proteinsREACTOMER-HSA-392499
    Post-translational protein modificationREACTOMER-HSA-597592
    DiseaseREACTOMER-HSA-1643685
    Diseases of signal transductionREACTOMER-HSA-5663202
    Signaling by WNT in cancerREACTOMER-HSA-4791275
    truncated APC mutants destabilize the destruction complexREACTOMER-HSA-4839744
    APC truncation mutants are not K63 polyubiquitinatedREACTOMER-HSA-5467333
    APC truncation mutants have impaired AXIN bindingREACTOMER-HSA-5467337
    AXIN mutants destabilize the destruction complex, activating WNT signalingREACTOMER-HSA-4839735
    AXIN missense mutants destabilize the destruction complexREACTOMER-HSA-5467340
    AMER1 mutants destabilize the destruction complexREACTOMER-HSA-4839748
    Truncations of AMER1 destabilize the destruction complexREACTOMER-HSA-5467348
    phosphorylation site mutants of CTNNB1 are not targeted to the proteasome by the destruction complexREACTOMER-HSA-4839743
    S45 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358751
    T41 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358752
    S37 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358749
    S33 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358747
    Misspliced GSK3beta mutants stabilize beta-cateninREACTOMER-HSA-5339716
    Signal TransductionREACTOMER-HSA-162582
    Signaling by WntREACTOMER-HSA-195721
    Degradation of beta-catenin by the destruction complexREACTOMER-HSA-195253
    Beta-catenin phosphorylation cascadeREACTOMER-HSA-196299
    TCF dependent signaling in response to WNTREACTOMER-HSA-201681
    Disassembly of the destruction complex and recruitment of AXIN to the membraneREACTOMER-HSA-4641262
    Deactivation of the beta-catenin transactivating complexREACTOMER-HSA-3769402
    Programmed Cell DeathREACTOMER-HSA-5357801
    ApoptosisREACTOMER-HSA-109581
    Apoptotic execution phaseREACTOMER-HSA-75153
    Apoptotic cleavage of cellular proteinsREACTOMER-HSA-111465
    DeubiquitinationREACTOMER-HSA-5688426
    Ovarian tumor domain proteasesREACTOMER-HSA-5689896
    Breast cancerKEGGko05224
    Breast cancerKEGGhsa05224

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    PharmGKB

    Entity IDNameTypeEvidenceAssociationPKPDPMIDs
    PA445381Adenomatous Polyposis ColiDiseaseLiterature, MultilinkAnnotationassociated23788249

    References

    Pubmed IDYearTitleCitations
    183376022008DNA methylation markers and early recurrence in stage I lung cancer.188
    186326332008Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer.177
    120452082002The 'just-right' signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade.133
    120938992002Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer.129
    194505122009A two-step model for colon adenoma initiation and progression caused by APC loss.127
    117513822001Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer.117
    155617722004Truncating APC mutations have dominant effects on proliferation, spindle checkpoint control, survival and chromosome stability.94
    160302542005APC and EB1 function together in mitosis to regulate spindle dynamics and chromosome alignment.93
    199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
    227040622012Epithelial to mesenchymal transition (EMT) biomarkers--E-cadherin, beta-catenin, APC and Vimentin--in oral squamous cell carcinogenesis and transformation.84

    Citation

    Jennifer S Tirnauer

    APC (adenomatous polyposis coli)

    Atlas Genet Cytogenet Oncol Haematol. 2005-03-01

    Online version: http://atlasgeneticsoncology.org/gene/118/apc

    Historical Card

    1998-04-01 APC (adenomatous polyposis coli) by  Richard Hamelin 

    INSERM U434, CEPH, 27, rue Juliette Dodu, 75010 Paris, France