Molecular Genetics Familial Adenomatous Polyposis (FAP), APC Deletion/Duplication

Familial adenomatous polyposis (FAP) is an autosomal dominant cancer syndrome caused largely by mutations in APC, and to a lesser degree, MUTYH. FAP patients develop hundreds of colorectal adenomas at a young age (often in the teenage years), as well as extracolonic polyps, cutaneous lesions, desmoids tumors, osteomas, and dental abnormalities, with an average age of diagnosis of 34.5-43 years. An attenuated form of FAP (AFAP) is similar to FAP, with a decidedly less severe phenotype (less than 100 adenomas), and diagnosed approximately 12 years later than an FAP patient. Other colorectal cancer syndromes have also been associated with mutations in APC such as Gardner syndrome and Turcot syndrome, which have slightly different phenotypes than FAP. Depending on the population studied, small germline mutations in APC account for 70-90% of FAP cases and 16% of AFAP cases while larger deletions and duplications of APC account for approximately 15% of FAP/AFAP cases. Mutations of MUTYH also account for approximately 30% of patients with an AFAP phenotype and 7-30% of patients with a FAP phenotype. While APC mutations manifest in an autosomal dominant manner, most patients with MUTYH defects have biallelic mutations. However there may be other genetic and environmental factors that play a role in the FAP/AFAP phenotypes.

Reasons for Referral:

• Identification of inherited genetic defects in APC in patients with FAP/AFAP characteristics or early onset colon cancer
• Confirmation of a suspected diagnosis with a positive family history of early onset colon cancer when a familial mutation is known
• Predispositional testing for asymptomatic family members with a positive family history of colorectal cancer

For detailed information and ordering instructions, please refer to Exon-centric deletion/duplication analysis (1340). Genes may be added or removed from the list below if clinically indicated.

 

1. Aretz S, et al. Large submicroscopic genomic APC deletions are a common cause of typical familial adenomatous polyposis. J Med Genet 2005; 42: 185-192.
2. Giardiello F, et al. AGA Technical Review on Hereditary Colorectal Cancer and Genetic Testing. Gastroenterology 2001; 121: 198-213.
3. Nielsen M, et al. Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis. Clin Genet 2007; 71: 427-433.