Adenomatous Polyposis Syndromes
MYH-associated polyposis syndrome (MAP)
Recently, the base-excision repair gene MYH has been identified as responsible for an autosomal recessive inherited syndrome associated with multiple adenomas and carcinoma. This constitutes a new paradigm in hereditary colorectal cancer, provided the other colorectal cancer syndromes have an autosomal dominant pattern of inheritance. The syndrome has been called MAP for MYH-associated polyposis syndrome.
In a population cohort study, this syndrome was present in 0,7% of all colorectal cancers. Patients with this syndrome present more than a 90-fold increased risk of colon cancer. The presence of more than 15 synchronous colorectal adenomas and a colorectal adenocarcinoma diagnosis before the age of 50 may be factors independently associated with the syndrome.
Genetic testing and MAP
As with all autosomal recessive inherited syndromes, the mutation has to be inherited from both paternal and maternal alleles. Since affected members typically skip a generation, siblings can be affected with cancer but not their parents.
The MYH gene is located in the short arm of chromosome 1 and is part of the DNA Base Excision Repair system. The enzyme coded by this gene removes 8-oxodG adducts from DNA that are incorporated as a result of reactive oxygen species (ROS) oxidation.
Biallelic MYH mutations account for 7% of FAP cases ( > 100 adenomas) without an identified germ-line mutation in the APC gene, and for 29 % of those patients with 15-100 adenomas. In those cases with a clinical phenotype characteristic of FAP or AFAP in which a mutation in the APC gene is not found, the alterations in MYH (MUTYH gene) should be studied. These biallelic mutations could be homozygous or compound heterozygous and, in the majority of cases, the disease-causing mutations are Y176C and G393D in Caucasians. A different causing mutation (E466X) has been described in Indian/Pakistani patients. Carrying monoallelic mutations doesn't seem to confer an increased risk for colorectal cancer development.
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