The prevalence of disease causing variants in the APC gene significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50-99 adenomas.
Hereditary polyposis syndromes in which APC gene germline mutations can lead to colorectal carcinogenesis are familial adenomatous polyposis (FAP), attenuated FAP (AFAP) and MUTYH-associated polyposis.
APC is associated with the familial adenomatous polyposis (FAP/AFAP) and MUTYH with the MUTYH-associated polyposis (MAP), while POLE and POLD1 mutations cause the polymerase proofreading-associated polyposis (PPAP).
There are two major hereditary colorectal cancer syndromes: Adenomatous Polyposis, secondary to APC germline alterations (FAP, Familial Adenomatous Polyposis) or secondary to MUTYH germline alterations (MAP, MUTYH associated Polyposis), and Lynch syndrome, associated with germline mutations in mismatch repair genes (MLH1, MSH2, MSH6 and PMS2).
MUTYH-associated polyposis showed the horizontal transmission expected for recessive inheritance (at variance with the dominant pattern seen with APC mutations).
Patients in whom no mutation is identified through this mutation protocol, may be sub-cohorts representing a different FAP pathogenesis including MYH associated polyposis and somatic cell mosaicism for APC gene mutations.
These results suggest that hypermutation of APC does not cause our patients' disease and strongly suggests that MAP is not a paradigm for the remaining MCRA patients.
Recently, biallelic germ line mutations in the MYH gene were found to be responsible for MYH-associated polyposis (MAP), an autosomal recessive predisposition to multiple colorectal polyps, often indistinguishable from the dominant familial adenomatous polyposis (FAP) syndrome caused by inherited APC mutations.
There was overlap between genetic pathways followed by each type of CRC, but significant differences included: increased frequency of K-ras mutation and reduced frequency of APC LOH in cancers from MAP, but not from multiple adenoma patients; reduced frequency of LOH in HNPCC CRCs; and increased MSI in CRCs from HNPCC, but not from FCC or multiple adenoma patients.
These results indicated that MYH-associated polyposis (MAP) is present in about 20% of Italian FAP/AAPC patients, in whom no germline APC mutation is detectable and showing a family history compatible with recessive inheritance, and in a small fraction of patients with colorectal adenomas in the general population.