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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Major Genetic Syndromes

Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP) continued...

AFAP is associated with particular subsets of APC mutations, including missense changes. Three groups of site-specific APC mutations causing AFAP have been characterized:[27,28,29,30,181,182]

  • Mutations associated with the 5' end of APC and exon 4 in which patients can manifest 2 to more than 500 adenomas, including the classic FAP phenotype and upper gastrointestinal polyps.
  • Exon 9–associated phenotypes in which patients may have 1 to 150 adenomas but no upper GI manifestations.
  • 3' region mutations in which patients have very few adenomas (<50).

APC gene testing is an important component of the evaluation of patients suspected of having AFAP.[140] It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided.[140] The role for and timing of risk-reducing colectomy in AFAP is controversial.[183] If germline APC mutation testing is negative in suspected AFAP individuals, genetic testing for MYH mutations may be warranted.[132]

Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[184,185] In the absence of family history of similarly affected relatives, the differential diagnosis may include AFAP (including MAP), LS, or an otherwise unclassified sporadic or genetic problem. A careful family history may implicate AFAP or LS.

MYH-Associated Polyposis (MAP)

MAP is an autosomal recessive inherited polyposis syndrome. The MYH gene was first identified in 2002 in three siblings with multiple colonic adenomas and CRC but no APC mutation.[137] MAP has a broad clinical spectrum. Most often it resembles the clinical picture of AFAP, but it has been reported in individuals with phenotypic resemblance to classical FAP and LS.[186] MAP patients tend to develop fewer adenomas at a later age than patients with APC mutations [135,187] and also carry a high risk of CRC (35%–53%).[5] This broad clinical presentation results from the MYH gene's ability to cause disease in its homozygous or compound heterozygous forms. Based on studies from multiple FAP registries, approximately 7% to 19% of patients with a FAP phenotype and without a detectable APC germline mutation carry biallelic mutations in the MYH gene.[5,135,188,189]

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