Aetiology

Familial adenomatous polyposis (FAP) and attenuated FAP are both caused by mutations in one allele of the adenomatous polyposis coli (APC) gene.[14]​ These germline mutations cause FAP to be inherited in an autosomal dominant pattern in the majority of cases; however, up to 30% of FAP probands have no family history of polyposis or colorectal cancer; these cases may be explained by somatic mosaicism in the APC gene.[2][3]

Mutations throughout the APC gene are associated with FAP, but mutations located in the 5' or 3' region of the gene are more commonly associated with attenuated FAP.[15]​ Some cases of adenomatous polyposis result from germline mutations in POLD1, POLE, or GREM1.[16][17][18][19]

Pathophysiology

APC, located on chromosome 5q21, functions as a tumour suppressor gene. Loss or inactivation of the second wildtype (functioning) allele of APC in somatic tissues such as the colon results in loss of the tumour suppressor function of APC in that tissue. APC suppresses tumour formation through its role as a scaffolding protein and its involvement in regulating the Wnt signalling pathway. By regulating the Wnt pathway, the APC protein controls beta-catenin degradation. When the APC protein function is lost, beta-catenin accumulates and alters the expression of the T-cell factor family of transcription factors. With this disruption of cell signalling and the cell-cycle control by inactivation of APC via mutation, the DNA of the colonic epithelial cells is vulnerable to additional mutations that precipitate tumourigenesis. This multistep process is termed the adenoma to carcinoma sequence.[20]​​[21][22]

Many genes are mutated during the adenoma to carcinoma sequence. The tumour suppressor genes p53 and SMAD4 are inactivated and fail to protect the DNA from further damage. Proto-oncogenes including K-ras are activated once they are mutated and stimulate tumour progression. Cyclo-oxygenase (COX)-2 is then stimulated, and its over-expression increases with tumour progression. COX-2 has therefore been the target of COX inhibitors designed to cause adenoma regression.[20]​​[21][22][23]

Classification

Severity of syndrome

  • FAP: autosomal-dominant colorectal cancer syndrome associated with more than 100 colorectal adenomas and nearly 100% risk for colorectal cancer by age 40 years if risk-reducing surgery is not performed.[1]​ Colorectal cancer arises in the left side of the colon or rectum in 70% of cases.[6]

  • Attenuated FAP: autosomal-dominant colorectal cancer syndrome associated with fewer than 100 colorectal adenomas and 80% risk for colorectal cancer by 60 years of age, in the absence of endoscopic or surgical intervention.[1][7]​ The onset of colorectal cancer is typically delayed by 10-20 years compared with patients with FAP, but rises sharply after the age of 40 years. Colorectal cancer typically arises in the right side of the colon.[11]

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