What mutation causes familial adenomatous polyposis (FAP)?

Familial Adenomatous Polyposis (FAP) is Caused by Mutations in the APC Gene

Familial adenomatous polyposis (FAP) is primarily caused by germline mutations in the APC gene located on the long arm of chromosome 5 (5q21-22). 1

Primary Genetic Cause

• Classical FAP is caused by mutations in the APC gene, which plays a central role in the development and homeostasis of the intestine and many other tissues 1
• The APC gene is located on chromosome 5q21-22 and mutations in this gene are detected in approximately two-thirds or more of families affected with FAP 1
• FAP follows an autosomal dominant inheritance pattern, meaning each child of an affected parent has a 50% chance of inheriting the predisposition 1
• Between one-third and half of new FAP cases represent de novo mutations of the APC gene, with no family history of the condition 1

Mutation Detection Rates

• APC mutations are found in approximately 80% of patients with 1,000 or more adenomas 1
• In patients with 100-999 adenomas, APC mutations are detected in about 56% of cases 1
• The mutation detection rate decreases to 10% in patients with 20-99 adenomas and 5% in patients with 10-19 adenomas 1

Alternative Genetic Causes

• In FAP-like cases where no APC mutation is identified, mutations in the MUTYH gene may explain a portion of cases, especially in those with attenuated disease 1
• MUTYH-associated polyposis (MAP) follows an autosomal recessive inheritance pattern, requiring bi-allelic mutations 1
• Bi-allelic MUTYH mutations are found in 26-29% of patients with 10-100 adenomas and in 7-29% of patients with 100-1000 adenomas 1

Genotype-Phenotype Correlations

• The severity of colonic polyposis correlates with the site of the mutation in the APC gene 1
• Mutations at codon 1309 of the APC gene can result in significant intrafamily and interfamily phenotypic variation, suggesting that environmental and/or other genetic factors play roles in the expression of germline APC mutations 2
• Pigmented ocular fundus lesions are strongly associated with mutations in codons 541-1309 3
• Multiplicity of extraintestinal manifestations is high with mutations in codons 1465,1546, and 2621 3

Clinical Implications

• Final diagnosis of FAP is achieved by discovery of a mutation in the APC gene 1
• If an APC mutation has been identified in a family, genetic testing can replace endoscopic screening for at-risk individuals 1
• Only mutation-positive individuals need endoscopic surveillance to evaluate adenoma development and to estimate the timing of prophylactic surgery 1
• The position of the APC mutation may influence surgical decisions, as it can correlate with the severity of rectal polyposis 1

Emerging Research

• Inactivation of promoter 1B of the APC gene can cause partial gene silencing and has been shown to be disease-causing in FAP 4
• Expression of transcripts from promoter 1B is generated at considerably higher levels compared to promoter 1A, demonstrating a previously unknown importance of promoter 1B in APC gene regulation 4

It's important to note that while APC mutations are the primary cause of FAP, other genetic factors are likely involved in the development of this condition, particularly in cases where no APC mutation is identified despite a clear clinical presentation of polyposis 1.