Molecular Genetics of MUTYH‐Associated Polyposis


MUTYH‐associated polyposis (MAP) is an autosomal recessive condition characterised by the development of multiple colon polyps and colorectal cancer (CRC). It is caused by biallelic germline mutations in the human mutY homologue (MUTYH) gene on 1p34.3. The MUTYH protein is a base excision repair glycosylase involved in the repair of oxidation of a guanine leading to 8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine. MUTYH recognises an oxoG:A mismatch and excises the undamaged adenine base using a base‐flipping mechanism.

Most carriers of biallelic MUTYH mutations develop between 10 and 500, predominantly adenomatous polyps and CRC, but a number of MAP patients have CRC without polyps. The lifetime CRC risk in MAP patients is between 40% and 100% in the absence of timely surveillance. The lifetime risk for duodenal cancer is approximately 4% and a modest, but significant increase in incidence has been shown for ovarian, bladder and skin cancer.

Key Concepts:

  • MUTYH‐associated polyposis (MAP) is an autosomal recessive inherited polyposis and CRC syndrome.

  • MAP is caused by mutations in both alleles of the MUTYH gene.

  • One of the key functions of the MUTYH protein is prevention of mutagenesis caused by oxidative DNA damage of guanine.

  • Loss of MUTYH activity leads to somatic G>T transversions.

  • In the North West (NW) European population, two founder missense mutations, the p.G396D and p.Y179C, compromise more than 90% of mutations reported.

  • A somatic hotspot KRAS2 mutation in codon 12 (c.34 G>T) is present in about half of MAP‐associated colon tumours.

Keywords: MUTYH‐associated polyposis; MUTYH gene; MAP; colorectal cancer; polyposis

Figure 1.

When a guanine is oxidated, a subsequent oxoG:A mismatch in the DNA template can lead to a G:C to T:A transversion in the next round of replication. MUTYH – after recognising the oxoG:A mismatch – excises the adenine base using a base‐flipping mechanism. DNA polymerases can subsequently restore an oxoG:C pair that can be acted on by another BER‐glycosylase, OGG1, to replace the oxidised guanine with a guanine. Reproduced by permission of Bohn Stafleu van Loghum.



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Further Reading

David SS, O'Shea VL and Kundu S (2007) Base‐excision repair of oxidative DNA damage. Nature 447: 941–950.

Sampson JR and Jones N (2009) MUTYH‐associated polyposis. Best Practice & Research Clinical Gastroenterology 23: 209–218.

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Nielsen, Maartje, Aretz, Stefan, and Sampson, Julian R(Mar 2013) Molecular Genetics of MUTYH‐Associated Polyposis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024293]