Familial adenomatous polyposis pathophysiology: Difference between revisions

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Revision as of 16:03, 24 January 2018

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

Familial adenomatous polyposis may have different inheritance patterns and genes involved.
Familial adenomatous polyposis is due to mutations in different genes, including:
- APC gene, which is located on chromosome 5 in band q21 or band q22 (5q21-q22)
- MUTYH gene, which is located on chromosome 1 between bands p34.2 and p32.1 (5p34.3-p32.1)

Familial adenomatous polyposis has autosomal dominant inheritance pattern if it results from mutations in the APC gene.
Familial adenomatous polyposis has autosomal dominant recessive pattern if it results from mutations in the MUTYH gene.

Associated Conditions

Familial adenomatous polyposis is associated with other conditions including:^[1]

Duodenum adenoma
Stomach adenoma
Desmoid tumor
- The risk is approximately 6%-12%.
- It mostly happens in small bowel mesentery.
Periampullary cancer
- The risk is approximately 10%.
Thyroid cancer
Pancreatic cancer

Gross Pathology

Microscopic Pathology

References

↑ Beech D, Pontius A, Muni N, Long WP (2001). "Familial adenomatous polyposis: a case report and review of the literature". J Natl Med Assoc. 93 (6): 208–13. PMC 2594024. PMID 11446392.

[pmid11446392-1] Beech D, Pontius A, Muni N, Long WP (2001). "Familial adenomatous polyposis: a case report and review of the literature". J Natl Med Assoc. 93 (6): 208–13. PMC 2594024. PMID 11446392.

[1]

@@ Line 13: / Line 13: @@
 ==Genetics==
-* Familial adenomatous polyposis is an autosomal dominant inherited syndrome.
+* Familial adenomatous polyposis may have different [[Heredity|inheritance]] patterns and [[Gene|genes]] involved.
-* FAP is due to mutations in the ''[[APC (gene)|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).
+* Familial adenomatous polyposis is due to mutations in different genes, including:
+** [[APC (gene)|''APC'' gene]], which is located on [[Chromosome 5 (human)|chromosome 5]] in band q21 or band q22 (5q21-q22)
+** [[MUTYH|''MUTYH'' gene]], which is located on [[Chromosome 1 (human)|chromosome 1]] between bands p34.2 and p32.1 (5p34.3-p32.1)
-* ''[[APC (gene)|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.
+* Familial adenomatous polyposis has [[autosomal dominant inheritance]] pattern if it results from mutations in the [[APC (gene)|''APC'' gene]].
+* Familial adenomatous polyposis has autosomal dominant recessive pattern if it results from mutations in the [[MUTYH|''MUTYH'' gene]].
-* Although the polyps are inherently benign, the first step of the [[Knudson hypothesis|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 [[epithelium|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 [[mutation]]s 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 [[proband]]s.<ref>{{cite journal |author=Reyes Moreno J, Ginard Vicens D, Vanrell M, ''et al'' |title=[Impact of a registry on the survival familial adenomatous polyposis.] |language=Spanish; Castilian |journal=Medicina clínica |volume=129 |issue=2 |pages=51-2 |year=2007 |pmid=17588361 |doi=}}</ref> The [http://www.polyposisregistry.org.uk/index.htm St. Mark's polyposis registry] is the oldest in the world, started in 1924, and many other [[polyposis registries]] now exist.
 ==Associated Conditions==
 Familial adenomatous polyposis is associated with other conditions including:<ref name="pmid11446392">{{cite journal |vauthors=Beech D, Pontius A, Muni N, Long WP |title=Familial adenomatous polyposis: a case report and review of the literature |journal=J Natl Med Assoc |volume=93 |issue=6 |pages=208–13 |year=2001 |pmid=11446392 |pmc=2594024 |doi= |url=}}</ref>