Familial adenomatous polyposis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Mohamad Alkateb, MBBCh [3]
Overview
The development of familial adenomatous polyposis is the result of multiple genetic mutations. Genes involved in the pathogenesis of familial adenomatous polyposis include APC and MUTYH genes. Many patients have a positive family history of colorectal cancer or polyps. However, some of them may have no previous family history. Loss of APC gene function is believed to be the first event in pathogenesis of colon cancer leading to formation of an adenoma. Three hundred mutations of APC gene have been discovered for familial adenomatous polyposis. These mutations have premature stop codons and lead to a truncated protein. Familial adenomatous polyposis has autosomal dominant inheritance pattern if it results from mutations in the APC gene and autosomal recessive inheritance pattern if it results from mutations in the MUTYH gene. Mutation is found in 6% of Ashkenazi Jews. Familial adenomatous polyposis is associated with different malignancies including stomach cancer, periampullary cancer, pancreatic cancer, hepatoblastoma, bile duct cancer, papillary thyroid cancer, and medulloblastoma. Duodenal adenoma, adrenal masses, desmoid tumor, osteomas, congenital hypertrophy of the retinal pigment epithelium, epidermoid cysts, and fibromas are associated with familial adenomatous polyposis. On gross pathology, numerous polyps are characteristic finding of familial adenomatous polyposis.
Pathophysiology
Pathogenesis
- Familial adenomatous polyposis is a genetic disorder that is caused by mutation in APC and MUTYH genes.[1]
- Many of patients have a positive family history of colorectal cancer or polyps. However, some of them have no previous family history.
- Germline mosaicism might be responsible for sudden manifestation of familial adenomatous polyposis.[2]
- Loss of APC gene function is believed to be the first event in pathogenesis of colon cancer leading to formation of an adenoma.[3]
Genetics
- Familial adenomatous polyposis may have different inheritance patterns and genes involved.[4]
- Familial adenomatous polyposis is due to mutations in different genes, including:[5][6]
- APC gene, which is located on chromosome 5 in band q21 or band q22 (5q21-q22)
- APC gene is a tumor suppressor gene that has an essential role in cell adhesion, signal transduction and transcriptional regulation.
- Three hundred mutations of APC gene have been discovered for familial adenomatous polyposis.
- They have premature stop codons and lead to a truncated protein.
- Mutation is seen in 6% of Ashkenazi Jews.[7]
- Mutation is seen in about 28% of those of Ashkenazi descent with a family history of colorectal cancer.
- MUTYH gene, which is located on chromosome 1 between bands p34.2 and p32.1 (1p34.3-p32.1)
- APC gene, which is located on chromosome 5 in band q21 or band q22 (5q21-q22)
- Familial adenomatous polyposis has autosomal dominant inheritance pattern if it results from mutations in the APC gene.
- Familial adenomatous polyposis has autosomal recessive inheritance pattern if it results from mutations in the MUTYH gene.
Associated Conditions
Familial adenomatous polyposis is associated with other gastrointestinal and extra intestinal conditions including:[8][9][1]
Gastrointestinal conditions
- Duodenal adenoma
- Stomach cancer
- The risk is approximately 0.5%.
- Periampullary cancer
- The risk is approximately 10%.
- Pancreatic cancer
- The risk is approximately 2%.
- Hepatoblastoma
- The risk is approximately 1.5%.
- Bile duct cancer
Extra intestinal conditions
- Adrenal masses
- Desmoid tumor
- The risk is approximately 10% to 20%.
- It mostly happens in small bowel mesentery.
- Papillary thyroid cancer
- The risk is approximately 2% to 25%.
- Medulloblastoma
- Osteomas
- It is a benign bony growth mainly on jaw
- Congenital hypertrophy of the retinal pigment epithelium
- Epidermoid cysts and fibromas
Gross Pathology
- On gross pathology, numerous polyps are characteristic findings of familial adenomatous polyposis.
Microscopic Pathology
- On microscopic histopathological analysis, serration of the luminal surface and normal nuclei are characteristic findings of hyperplastic polyps.
- On microscopic histopathological analysis, branched tubular glands are characteristic findings of tubular adenoma.
- On microscopic histopathological analysis, long finger-like projections are characteristic findings of villous adenoma.
- On microscopic histopathological analysis, branched and dilated glands, no cytological atypia, eosinophilic cytoplasm, and luminal epithelial tufting are characteristic findings of sessile serrated adenoma.
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References
- ↑ 1.0 1.1 King, John E.; Dozois, Roger R.; Lindor, Noralane M.; Ahlquist, David A. (2000). "Care of Patients and Their Families With Familial Adenomatous Polyposis". Mayo Clinic Proceedings. 75 (1): 57–67. doi:10.4065/75.1.57. ISSN 0025-6196.
- ↑ Nieuwenhuis, M.H.; Vasen, H.F.A. (2007). "Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): A review of the literature". Critical Reviews in Oncology/Hematology. 61 (2): 153–161. doi:10.1016/j.critrevonc.2006.07.004. ISSN 1040-8428.
- ↑ Half, Elizabeth; Bercovich, Dani; Rozen, Paul (2009). "Familial adenomatous polyposis". Orphanet Journal of Rare Diseases. 4 (1): 22. doi:10.1186/1750-1172-4-22. ISSN 1750-1172.
- ↑ Brensinger JD, Laken SJ, Luce MC, Powell SM, Vance GH, Ahnen DJ, Petersen GM, Hamilton SR, Giardiello FM (1998). "Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene". Gut. 43 (4): 548–52. PMC 1727294. PMID 9824584.
- ↑ Iaquinto, Gaetano; Fornasarig, Mara; Quaia, Michele; Giardullo, Nicola; D'Onofrio, Vittorio; Iaquinto, Salvatore; Di Bella, Simone; Cannizzaro, Renato (2008). "Capsule endoscopy is useful and safe for small-bowel surveillance in familial adenomatous polyposis". Gastrointestinal Endoscopy. 67 (1): 61–67. doi:10.1016/j.gie.2007.07.048. ISSN 0016-5107.
- ↑ Amos-Landgraf JM, Kwong LN, Kendziorski CM, Reichelderfer M, Torrealba J, Weichert J, Haag JD, Chen KS, Waller JL, Gould MN, Dove WF (2007). "A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer". Proc. Natl. Acad. Sci. U.S.A. 104 (10): 4036–41. doi:10.1073/pnas.0611690104. PMC 1805486. PMID 17360473.
- ↑ Roy, Hemant K.; Khandekar, Janardan D. (2012). "APC Gene Testing for Familial Adenomatosis Polyposis". JAMA. 308 (5): 514. doi:10.1001/jama.2012.9516. ISSN 0098-7484.
- ↑ 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.
- ↑ Kennedy, Raelene D.; Potter, D. Dean; Moir, Christopher R.; El-Youssef, Mounif (2014). "The natural history of familial adenomatous polyposis syndrome: A 24year review of a single center experience in screening, diagnosis, and outcomes". Journal of Pediatric Surgery. 49 (1): 82–86. doi:10.1016/j.jpedsurg.2013.09.033. ISSN 0022-3468.
- ↑ "File:Congenital hypertrophy of the retinal pigment epithelium.jpg - Wikimedia Commons".
- ↑ "File:Familial Adenomatous Polyposis intestine.jpg - Wikimedia Commons".
- ↑ [+https://commons.wikimedia.org/w/index.php?curid=63631954 "File:Familial adenomatous polyposis.jpg - Wikimedia Commons"] Check
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