APC encodes a tumor suppressor protein. The APC gene product indirectly regulates transcription of a number of critical cell proliferation genes, through its interaction with the transcription factor β-catenin. APC binding to β-catenin leads to ubiquitin-mediated β-catenin destruction; loss of APC function increases transcription of β-catenin targets. APC is involved in processes including cell migration and adhesion, transcriptional activation, and apoptosis.
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. 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 mutations: APC is one of the most frequently mutated genes in tumors. Alterations have been observed in small and large intestine, stomach, pancreas, liver, soft tissues, urinary tract, ovary, adrenal gland, thyroid, upper aerodigestive tract… Over 60% of somatic mutations occur within the mutation cluster region (MCR) (amino acids 1286-1513). Both copies of the APC gene are mutated in 80% of sporadic colorectal tumors. Sporadic colorectal cancer is the third most frequent cancer in the world. Loss of normal APC function is known to be an early event in both familial and sporadic colorectal cancer, occurring at the pre-adenoma stage. Current discussion is focused on whether loss of APC function precedes, follows, or is entwined with chromosomal instability.
As mentioned above, germline defects in APC are a cause of FAP, which is characterized by adenomatous polyps of the colon and rectum, but also of upper gastrointestinal tract (ampullary, duodenal and gastric adenomas). FAP is a viciously premalignant disease with one or more polyps progressing through dysplasia to malignancy in untreated gene carriers with a median age at diagnosis of 40 years. Disease-associated mutations tend to be clustered in the MCR and result in a truncated protein product.
FAP encompasses other disease syndromes with extra-colonic manifestations: Gardner Syndrome and Turcot Syndrome.
In Gardner Syndrome, patients with mutated APC may develop the following extra-intestinal manifestations: cancers of stomach, duodenum, pancreas, biliary tree, and gallbladder; hepatoblastoma; desmoid tumors; osteomas and dental abnormalities; epidermoid cysts and other skin abnormalities.
Turcot syndrome is an autosomal dominant disorder in which APC mutations lead to malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots.
Defects in APC are also a cause of hereditary desmoid disease (HDD), an autosomal dominant disorder with 100% penetrance and possible variable expression among affected relatives. HDD patients show multifocal fibromatosis of the paraspinal muscles, breast, occiput, arms, lower ribs, abdominal wall, and mesentery. Desmoid tumors appears also as a complication of FAP.
Celecoxib is approved as an adjunctive chemopreventive agent in adults with familial adenomatous polyposis (FAP).
References (open access):
APC-Associated Polyposis Conditions. Burt RW, Jasperson KW. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. SourceGeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-1998 Dec 18 [updated 2008 Jul 24].
Analysis of rare APC variants at the mRNA level: six pathogenic mutations and literature review. Kaufmann A, Vogt S, Uhlhaas S, Stienen D, Kurth I, Hameister H, Mangold E, Kötting J, Kaminsky E, Propping P, Friedl W, Aretz S. J Mol Diagn. 2009 Mar;11(2):131-9.