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Hereditary colon cancer is a heterogeneous conglomeration of genetic defects that are mostly autosomal dominant in nature and lead to variable risk of colon cancer and other associated cancers. Some of these syndromes are characterized by the formation of traditional adenomas and are caused by defects in tumor suppressor genes and others are in mismatch repair genes. The most common of these include mutations in the tumor suppressor adenomatous polyposis coli (APC) gene that is associated with familial polyposis. Genetic defects in tumor mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) are also associated with the development of adenomas, and these occur in multiple genes that are associated with tumors that have high levels of microsatellite instability (MSI). Finally, there is a group of less common genetic defects that result in hamartomatous polyposis syndromes such as juvenile polyposis and Peutz-Jeghers syndrome, to name the two most common. We will outline the genetic defects, epidemiology, diagnosis, clinical manifestations, and clinical management for these syndromes.



Familial adenomatous polyposis (FAP) is an inherited condition characterized by thousands of polyps in the colon. FAP occurs with a frequency of about 1:10,000 to 1:18,000 live births in Northern Europe and other similar Caucasian populations.1-3 It accounts for less than 1% of all colorectal cancers. Males and females are affected equally.


FAP is an autosomal dominant colorectal cancer syndrome caused by a germline mutation in the APC gene, located on chromosome 5q21-22. The APC gene is a tumor suppressor gene that functions by suppressing the formation of adenomas in the colon and tumors elsewhere in the body. Approximately 10% to 25% of germline APC mutations are new in individuals without a family history of FAP.3-5 There is nearly 100% penetrance of the colonic manifestations of FAP but variable penetrance of the extracolonic manifestations of the disease.6

Patients with FAP who inherit a single APC mutation acquire a somatic mutation (or “second hit”) in the second allele of the APC gene. A cell with this functional loss of the APC gene has no functional APC protein. This leads to defects in the Wnt signaling pathway, abnormal intracellular accumulation of beta-catenin, unregulated cell growth and division, and formation of adenomas.7,8 Over 1000 different mutations in the APC gene associated with FAP have been described, and the location of the mutation may influence the phenotypic expression. In other words, there is variable phenotypic expression depending on the location of the mutation in the gene.9

For example, patients with mutations near codon 1300 generally develop particularly severe disease with over 1000 polyps and earlier cancer onset.9,10 Attenuated FAP (<100 colorectal adenomas) is associated with mutations before codon 157 and after codon 1595.10 Congenital hypertrophy of the retinal ...

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