Mutyh-associated polyposis (map) D12.6

Autosomal-recessive inherited adenomatous polyposis Disease which, like familial adenomatous polyposis (FAP), is characterized by the occurrence of multiple polyps of the colon (histologically mostly adenomas). MUTYH is the acronym for "MutY DNA glycosylase" of a DNA glycolase.

1% of the population are carriers of the MUTYH gene mutation. The main consequence of the inheritance is that - in contrast to FAP - children can be genetically burdened without the parents showing phenotypic signs. However, both parents must be carriers of the genetic make-up. As a result of the inheritance, siblings of a MAP patient have a 25% risk of also being affected by this genetic disease. Children of a MAP patient are always carriers of this hereditary disease.

Children of a MAP patient therefore have a 0.5% probability (homozygous genetic material and heterozygous genetic material; 1% that two possible genotypes reduce to 0.5%).

Both parents of the patients only carry the mutated gene on one gene copy, the other gene copy is unchanged and can compensate for the mutation. They are therefore healthy, but so-called heterozygous carriers. The siblings of a person with the disease have a 25% risk of also developing the disease.

Mutation in the MUTYH gene (MYH gene) on chromosome 1p34.1. The MUTYH gene encodes a protein, a glycosylase, which is localized in the cell nucleus and the mitochondria of the cell and repairs DNA damage. MUTYH is a component of a base excision repair system that protects genomic information from oxidative damage.

The base pairs usually only occur in two forms: adenine with thymine and guanine with cytosine. As a result of oxidative damage, guanine can form a base pair with adenine. The MUTYH glycosylase recognizes this mismatch and repairs it. When MUTYH is affected by a biallelic germline mutation, this leads to mutation of cancer-related genes such as the APC and/or KRAS genes through a G-to-T transversionThe MUTYH glycosylase is overexpressed in CD4-T cells, in the prostate, colon and rectum.

The polyposis syndrome often phenotypically resembles an attenuated form of familial adenomatous polyposis. Mutations in both alleles of the gene are required for the development of the disease, but carriers of monoallelic mutations are found to have an increased risk of developing colorectal cancer (Toboeva MK et al. 2019). In Caucasian patients, the mutations c.536A>G (Y179C) and c.1187G>A (G396D) are frequently detected. In the Asian population, Y179C and G396D are rare, while other variants are considered the main causes of MAP.

The mean age of onset of colon cancer (especially in the proximal part of the colon) with MAP is 50 years. They develop preferentially in the proximal part of the colon.

A homozygous carrier of a MUTYH gene mutation is recommended to undergo regular colonoscopies from the age of 30.

There is a high risk of degeneration into a colorectal carcinoma.

As a rule, the clinical course is similar to that of the attenuated, mild form of FAP (attenuated FAP, also known as AFAP). As with AFAP, the polyps usually appear later and are less numerous than in classic FAP. The risk of developing colon cancer in untreated patients often does not increase until the 5th or 6th decade of life.

Adenomas in the duodenum occur less frequently in AFAP than in FAP. Extragastrointestinal symptoms are largely absent. In rare cases, colorectal carcinomas are associated with pilomatricomas.

Among the polyps, both hyperplastic and"sessile serrated adenomas (lesions)" are frequently found.

1. Nielsen M et al. (2011) MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol 79:1-16.
2. Papp J et al. (2015) Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary. Fam Cancer 15: 85-97.
3. Toboeva MK et al (2019) MutYH-associated polyposis. Ter Arkh 91:97-100.
4. Yamaguchi S et al. (2014) MUTYH-associated colorectal cancer and adenomatous polyposis. Surg Today 44:593-600.