MUTYH-ASSOCIATED POLYPOSIS (MAP)
Biallelic mutations in the MUTYH gene have been shown to be responsible for an autosomal recessive form of adenomatous polyposis. The MUTYH gene is involved in repair of oxidative DNA damage, and adenomas from affected patients show characteristic DNA repair errors. The number of colonic polyps in this condition tends to be between 15 and 200, significantly fewer than in classical FAP, although approximately 8 % of cases of polyposis with no detectable germline APC mutation, particularly cases with relatively few (100–500) polyps, have been found to carry biallelic mutations in the MUTYH gene (Sampson and Jones 2009). The disorder accounts for approximately 30 % of cases of attenuated polyposis, with 15–100 colonic adenomas; biallelic MUTYH mutations have been reported in 26–29 % of patients with 10–100 polyps and 7–29 % of patients with 100–1,000 polyps. Biallelic mutations have occasionally been reported in patients with fewer than 10 adenomas (Aretz et al. 2006; Brand et al. 2012; Al-Tassan et al. 2002; Sampson et al. 2003; Sieber et al. 2003a, b) and have been reported when a single colorectal cancer is the sole phenotype (Lubbe et al. 2009). Duodenal adenomas are found in 17–25 % of individuals with MAP; the lifetime risk of duodenal cancer is about 4 %. Osteomas and CHRPE have also been reported in MAP patients (Sieber et al. 2003a, b; Bartkova et al. 2008; Aretz et al. 2013). An extended spectrum of Tumours manifestations of biallelic mutations in MUTYH has been described (Vogt et al. 2009).
Management of patients with MUTYH-associated polyposis should be along the lines of FAP management, with upper GI surveillance, since affected individuals do have a risk of upper GI neoplasia. Screening should be initiated from the same age as recommended in AFAP (between 18 and 20 years). Because patients may develop only a few adenomas and CRC is often localized in the proximal colon, colonoscopy at 2-yearly intervals is preferable to sigmoidoscopy (Vasen et al. 2008).
Upper gastrointestinal endoscopy is advised, starting from 25 to 30 years of age, frequency depending on severity (Vasen et al. 2008). While this subject remains controversial, on balance, it seems that heterozygotes face little or no increased risk of GI polyps and colorectal cancer and do not require surveillance, but it is important to be certain that close relatives of affected individuals are offered genetic testing at least for the two common MUTYH mutations.
This rare, X-linked recessive disorder was described in a single family (two affected brothers) and was characterized by mental retardation, chromosome breakage, and a predisposition to T cell leukemia. It is suggested to be caused by a mutation of DNA polymerase alpha (Floy et al. 1990).