Table 10. Clinical Practice Guidelines for Colon Surveillance of BiallelicMYH-Associated Polyposis (MAP) continued...
Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, and thyroid and skin cancers including melanoma, squamous epithelial, and basal cell carcinomas.[194,195] Additionally, extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors.[135,195,196,197] Female MAP patients have an increased risk of breast cancer. These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or LS.[199,200]
Because MAP has an autosomal recessive inheritance pattern, siblings of an affected patient have a 25% chance of also carrying a biallelic MYH mutation and should be offered genetic testing. Similarly, testing can be offered to the partner of an affected patient so that the risk in their children can be assessed.
The clinical phenotype of monoallelic MYH mutations is less well characterized with respect to incidence and associated clinical phenotypes, and its role in pathogenesis of polyposis coli and colorectal carcinoma remains in dispute. Approximately 1% to 2% of the general population carry a deleterious mutation in MYH.[5,135,137] A 2011 meta-analysis found that monoallelic MYH mutation carriers are at modest increased risk of CRC (odds ratio [OR], 1.15; 95% CI, 0.98-1.36); however, given the rarity of monoallelic mutation carriers, they account for only a trivial proportion of all CRC cases. Although some studies have suggested screening these individuals on the basis of this modest increase in risk, others have suggested following screening recommendations for the general population.
MMR genes may interact with MYH and increase the risk of CRC. An association between MYH and MSH6 has been reported. Both proteins interact together in base excision repair processes. A study reported a significant increase of MSH6 mutations in monoallelic MYH mutation carriers with CRC compared to noncarriers (11.5% vs. 0%; P = .037).
Mut Y Homolog
The Mut Y homolog gene, which is also known as MUTYH and MYH, is located on chromosome 1p34.3-32.1. The protein encoded by MYH is a base excision repair glycosylase. It repairs one of the most common forms of oxidative damage. Over 100 unique sequence variants of MYH have been reported (Leiden Open Variation Database). A founder mutation with ethnic differentiation is assumed for MYH mutations. In Caucasian populations of northern European descent, two major variants, Y179C and G396D (formerly known as Y165C and G382D), account for 70% of biallelic mutations in MYH-associated polyposis patients, and 90% of these patients carry at least one of these mutations. Biallelic MYH mutations are associated with a 93-fold excess risk of CRC with near complete penetrance by age 60 years.