Familial adenomatous polyposis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]
Overview
Genes involved in the pathogenesis of familial adenomatous polyposis include APC and MUTYH genes.
Pathophysiology
Pathogenesis
Genetics
- FAP is due to mutations in the APC gene, which is located on chromosome 5 in band q21 or band q22 (5q21-q22), or in the MUTYH gene, which is located on chromosome 1 between bands p34.2 and p32.1 (5p34.3-p32.1).
- APC is a tumour suppressor gene, acting as a "gatekeeper" to prevent development of tumours. Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.
- Although the polyps are inherently benign, the first step of the two-hit hypothesis has already taken place: the inherited APC mutation. Often, the remaining "normal" allele is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in p53 or KRAS) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelial cells.
- The normal function of the APC gene product is still being investigated; it is present both the cell nucleus and the membrane. The canonical tumor-suppressor function of Apc is suppression of the oncogenic protein beta-catenin. However, other tumor-suppressor functions of Apc may be related to cell adherence and cytoskeleton organization.
- MUTYH encodes DNA repair enzyme MYH glycosylase. During normal cellular activities, guanine sometimes becomes altered by oxygen, which causes it to pair with adenine instead of cytosine. MYH glycosylase fixes these mistakes by base excision repair, such that mutations do not accumulate in the DNA and lead to tumor formation. When MYH glycosylase does not function correctly, DNA errors may accrue to initiate tumorigenesis with a clinical presentation similar to that in patients with Apc mutations.
- Familial adenomatous polyposis can have different inheritance patterns and different genetic causes. When this condition results from mutations in the APC gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.
- Mutations in the MUTYH gene are inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.
- Prenatal testing is possible if a disease-causing mutation is identified in an affected family member; however, prenatal testing for typically adult-onset disorders is uncommon and requires careful genetic counseling.
- Because of the genetic nature of FAP, polyposis registries have been developed around the world. The purpose of these registries is to increase knowledge about the transmissibility of FAP, but also to document, track, and notify family members of affected individuals. One study has shown that the use of a registry to notify family members (call-ups) significantly reduced mortality when compared with probands.[1] The St. Mark's polyposis registry is the oldest in the world, started in 1924, and many other polyposis registries now exist.