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MUTYH Associated Polyposis

Definition

  • Autosomal recessive syndrome characterized by germ line mutation of MUTYH (mutY homolog) resulting in intestinal adenomatous polyposis and a very high incidence of colorectal adenocarcinoma

Alternate/Historical Names

  • mutY homolog (gene encoding an enzyme active in DNA repair)
  • MYH associated polyposis (MAP)

Covered Separately:

Diagnostic Criteria

  • Biallelic germline mutations in MUTYH gene required
    • Autosomal recessive
    • Gene encodes an enzyme active in DNA repair
  • Clinical presentation similar to attenuated familial adenomatous polyposis
    • Usually 20-100
    • Usually appear in late childhood or later
  • Nearly universal development of colorectal adenocarcinoma
    • Evenly distributed left vs. right colon
    • Histologically indistinguishable from sporadic carcinomas
      • Usually low grade
    • 50% of patients present with carcinoma
    • Some suggestion that carriers of the trait may have a moderately increased incidence of carcinoma
  • Extra-colorectal abnormalities infrequent
    • Duodenal adenomas 18% incidence
      • Carcinoma very rare
    • Ovary, bladder, skin and breast cancers reported to be significantly increased (Vogt 2009)
    • Gastric and thyroid cancers have been reported
      • Not clear if there is an association
  • 18-30% of attenuated FAP patients that lack germ line APC mutations have MUTYH associated polyposis

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates : 1/31/10, 11/13/11

Supplemental studies

Immunohistology

  • One report shows sensitive and specific staining for MUTYH protein
    • Normal patients show cytoplasmic and nuclear staining
    • Patients with biallelic germline mutations show granular cytoplasmic staining but negative nuclei
      • Apical and/or subapical cytoplasm stains
      • Both normal and neoplastic tissue show this pattern

Genetic testing

  • PCR analysis employed to determine presence of mutations in MUTYH gene

Differential Diagnosis

MUTYH Associated Polyposis Attenuated Familial Adenomatous Polyposis
Germline mutation detected in MUTYH gene No MUTYH mutation
No germline APC mutation May have detectable APC mutation (10% of cases)
Autosomal recessive Autosomal dominant
18-30% of APC mutation negative attenuated FAP may instead be due to MUTYH mutation

 

MUTYH Associated Polyposis HNPCC
Family history of polyps and colorectal carcinoma only May have family history of characteristic associated neoplasms
Duodenal adenoma in 18% Duodenal adenoma rare
Germline mutation detected in MUTYH gene No MUTYH mutation
No evidence of mismatch repair deficiency Genetic and immunohistologic evidence of mismatch repair deficiency
Autosomal recessive Autosomal dominant
MUTYH associated polyposis may be very difficult to distinguish clinically from HNPCC as it has fewer adenomas and later presentation and frequent right sided carcinoma

Clinical

  • Genetic counseling should be offered before genetic testing is performed
  • Autosomal recessive with unknown penetrance
  • Mean age of carcinoma is 45 years
  • Colectomy with constant surveillance of rectum or complete proctocolectomy removes the threat of colorectal carcinoma
    • Extra-colorectal neoplasms very rare
  • Screening
    • If MUTYH mutation is identified, screen positive family members starting at age 10
    • If mutation not identified, screen all family members from age 10
    • All patients diagnosed with MAP require upper GI screening

Bibliography

  • Bosman FT, Carneiro F, Hruban RH, Thiese ND (Eds). WHO Classifiication of Tumors of the Digestive System, IARC, Lyon 2010.
  • Desai TK, Barkel D. Syndromic colon cancer: lynch syndrome and familial adenomatous polyposis. Gastroenterol Clin North Am. 2008 Mar;37(1):47-72.
  • Gatalica Z, Torlakovic E. Pathology of the hereditary colorectal carcinoma. Fam Cancer. 2008;7(1):15-26.
  • Galiatsatos P, Foulkes WD. Familial adenomatous polyposis. Am J Gastroenterol. 2006 Feb;101(2):385-98.
  • Jass JR. Colorectal polyposes: from phenotype to diagnosis. Pathol Res Pract. 2008;204(7):431-47.
  • Sampson JR, Dolwani S, Jones S, Eccles D, Ellis A, Evans DG, Frayling I, Jordan S, Maher ER, Mak T, Maynard J, Pigatto F, Shaw J, Cheadle JP. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet. 2003 Jul 5;362(9377):39-41.
  • Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, Bisgaard ML, Orntoft TF, Aaltonen LA, Hodgson SV, Thomas HJ, Tomlinson IP. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med. 2003 Feb 27;348(9):791-9.
  • Aretz S, Uhlhaas S, Goergens H, Siberg K, Vogel M, Pagenstecher C, Mangold E, Caspari R, Propping P, Friedl W. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer. 2006 Aug 15;119(4):807-14.
  • O'Shea AM, Cleary SP, Croitoru MA, Kim H, Berk T, Monga N, Riddell RH, Pollett A, Gallinger S. Pathological features of colorectal carcinomas in MYH-associated polyposis. Histopathology. 2008 Aug;53(2):184-94.
  • Croitoru ME, Cleary SP, Berk T, Di Nicola N, Kopolovic I, Bapat B, Gallinger S. Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients. J Surg Oncol. 2007 May 1;95(6):499-506.
  • Di Gregorio C, Frattini M, Maffei S, Ponti G, Losi L, Pedroni M, Venesio T, Bertario L, Varesco L, Risio M, Ponz de Leon M. Immunohistochemical expression of MYH protein can be used to identify patients with MYH-associated polyposis. Gastroenterology. 2006 Aug;131(2):439-44.
  • Vogt S, Jones N, Christian D, Engel C, Nielsen M, Kaufmann A, Steinke V, Vasen HF, Propping P, Sampson JR, Hes FJ, Aretz S. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10
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