MUTYH-Associated Polyposis (MAP)

Identity

Other names	MYH associated polyposis
Atlas_Id	10092
Genes implicated in	MUTYH
Note	MAP is a recently described condition predisposing to colorectal cancer, caused by germline mutations in the base excision repair (BER) gene MUTYH (MYH). The first description of an affected family was provided in 2002.
Inheritance	Autosomal recessive. Heterozygote frequency in the general population is currently estimated as 0.01-0.02.

Clinics

Phenotype and clinics	The phenotype is often undistinguishable from that of autosomal dominant familial adenomatous polyposis (FAP) caused by mutations in APC gene. The number of adenomas is often lower in MAP (from 5 to more than 100), and affected patients are often sporadic cases. Biallelic MUTYH mutations have also been detected in patients affected with early-onset colorectal cancer (CRC) without polyps and in one with more than 1000 polyps. Cancers are more frequently located in the proximal side of the colon compared to APC-related FAP. Generally, mean age at diagnosis of MAP is 48-56 years, later than in APC-related FAP. A number of extracolonic manifestations have been observed, although their incidence is not yet well established. These include manifestations that are also associated with APC-related FAP, such as duodenal polyposis, duodenal cancer, osteomas, dental cysts and congenital hypertrophy of the retinal pigment epithelium. Breast cancer and thyroid cancer, and cutaneous tumors (pilomatricomas and sebaceous gland tumors) have also been reported.
Neoplastic risk	Penetrance of CRC is approximately 100% by age 65 years. Approximately 50% of patients present with CRC at the time of diagnosis. CRC risk in heterozygotes is not defined: some authors believe that monoallelic mutations may act as low penetrance alleles, increasing CRC risk, but larger studies with sufficient statistical power are necessary to accurately estimate the magnitude of such risk, if any.
Treatment	No specific screening guidelines have yet been established. Periodic colonoscopy of the entire colon should be offered to biallelic mutations carriers. Prophylactic colectomy should be considered when number, size and/or dysplasia of the polyps make continued surveillance unmanageable. Upper gastrointestinal surveillance is also indicated. Parents and children of individuals with biallelic mutations are obligate carriers of at least one MUTYH mutation. A baseline colonscopy has been suggested for these carriers, and, if findings are negative, screening should be repeated every 3-5 years.

Genes involved and Proteins

Gene Name	MUTYH (human MutY homologue)
Alias	MYH MYHbeta MutYhomolog (hMYH) MutY (E.Coli) homolog mutY homolog
Location	1p34.3-p32.1

Protein
Note	MUTYH glycosylase
Description	MUTYH is a DNA glycosylase that plays a key role in BER-mediated removal of 8-oxoG:A mismatches.

Mutations
Note	Most reported mutations in this gene cause production of a nonfunctional or low-functioning glycosylase enzyme. The two most common mutations in Caucasians, accounting for about 75%-80% of mutant alleles, are Y165C (or Tyr165Cys) and G382D (or Gly382Asp).

Bibliography

Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors.

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Nature genetics. 2002 ; 30 (2) : 227-232.

PMID 11818965

MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.

Aretz S, Uhlhaas S, Goergens H, Siberg K, Vogel M, Pagenstecher C, Mangold E, Caspari R, Propping P, Friedl W

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PMID 16557584

A kindred with MYH-associated polyposis and pilomatricomas.

Baglioni S, Melean G, Gensini F, Santucci M, Scatizzi M, Papi L, Genuardi M

American journal of medical genetics. Part A. 2005 ; 134 (2) : 212-214.

PMID 15690400

Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.

Croitoru ME, Cleary SP, Di Nicola N, Manno M, Selander T, Aronson M, Redston M, Cotterchio M, Knight J, Gryfe R, Gallinger S

Journal of the National Cancer Institute. 2004 ; 96 (21) : 1631-1634.

PMID 15523092

Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients.

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PMID 12937124

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PMID 15931596

Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer.

Fleischmann C, Peto J, Cheadle J, Shah B, Sampson J, Houlston RS

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PMID 14991577

Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas.

Gismondi V, Meta M, Bonelli L, Radice P, Sala P, Bertario L, Viel A, Fornasarig M, Arrigoni A, Gentile M, Ponz de Leon M, Anselmi L, Mareni C, Bruzzi P, Varesco L

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PMID 14999774

Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers.

Halford SE, Rowan AJ, Lipton L, Sieber OM, Pack K, Thomas HJ, Hodgson SV, Bodmer WF, Tomlinson IP

The American journal of pathology. 2003 ; 162 (5) : 1545-1548.

PMID 12707038

Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations.

Kairupan CF, Meldrum CJ, Crooks R, Milward EA, Spigelman AD, Burgess B, Groombridge C, Kirk J, Tucker K, Ward R, Williams R, Scott RJ

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PMID 15761860

Is prophylactic colectomy indicated in patients with MYH-associated polyposis?

Leite JS, Isidro G, Martins M, Regateiro F, Albuquerque O, Amaro P, Romãozinho JM, Boavida G, Castro-Sousa F

Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2005 ; 7 (4) : 327-331.

PMID 15932553

Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway.

Lipton L, Halford SE, Johnson V, Novelli MR, Jones A, Cummings C, Barclay E, Sieber O, Sadat A, Bisgaard ML, Hodgson SV, Aaltonen LA, Thomas HJ, Tomlinson IP

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PMID 14633673

Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP).

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PMID 16140997

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Ponti G, Ponz de Leon M, Maffei S, Pedroni M, Losi L, Di Gregorio C, Gismondi V, Scarselli A, Benatti P, Roncari B, Seidenari S, Pellacani G, Varotti C, Prete E, Varesco L, Roncucci L

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PMID 16207212

MutYH (MYH) and colorectal cancer.

Sampson JR, Jones S, Dolwani S, Cheadle JP

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PMID 16042573

Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.

Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, Bisgaard ML, Orntoft TF, Aaltonen LA, Hodgson SV, Thomas HJ, Tomlinson IP

The New England journal of medicine. 2003 ; 348 (9) : 791-799.

PMID 12606733

A comparison of the phenotype and genotype in adenomatous polyposis patients with and without a family history.

Truta B, Allen BA, Conrad PG, Weinberg V, Miller GA, Pomponio R, Lipton LR, Guerra G, Tomlinson IP, Sleisenger MH, Kim YS, Terdiman JP

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PMID 15951963

High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis.

Venesio T, Molatore S, Cattaneo F, Arrigoni A, Risio M, Ranzani GN

Gastroenterology. 2004 ; 126 (7) : 1681-1685.

PMID 15188161

MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps.

Wang L, Baudhuin LM, Boardman LA, Steenblock KJ, Petersen GM, Halling KC, French AJ, Johnson RA, Burgart LJ, Rabe K, Lindor NM, Thibodeau SN

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PMID 15236166

Germline mutations in the MYH gene in Swedish familial and sporadic colorectal cancer.

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Citation

This paper should be referenced as such :

Toschi, B ; Genuardi, M

MAP (MUTYH-Associated Polyposis )

Atlas Genet Cytogenet Oncol Haematol. 2006;10(4):300-301.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/MAPID10092.html

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