Molecular genetic and phenotypic characteristics of patients with adenomatous colorectal polyposis

Familial adenomatous polyposis (FAP), M(y"TY7-/-associated polyposis (MAP) and Hereditary non-polyposis colorectal cancer (HNPCC) are rare inherited colorectal cancer (CRC) predisposition syndromes resulting from mutations in APC, MUTYH and mismatch repair (MMR) genes, respectively. Mutational analysis of APC and MUTYH in 92 colorectal polyposis families living in Wales identified a genetic defect in 85 families (92%). Seventy unrelated cases (70/92, 76%) harboured pathogenic mutations in APC and biallelic MUTYH mutations were identified in 15 families. No pathogenic mutations could be detected in seven index patients without a dominant family history who had tens to hundreds of colorectal polyps with or without CRC. A European collaborative project established a cohort of 237 MAP patients. Analysis of MUTYH mutations in 182 unrelated MAP index cases highlighted the need for ORF sequencing as 17% (31/182) did not carry either of the common non-Asian mutations (Y176C and G393D). Fifty-eight percent of the MAP patient cohort (138/237) developed CRC and 36% (49/138) had more than one CRC. Retrospective assessment of medical records indicated that MAP patients are not at increased risk of cancers outside the Gl tract. The mean age at presentation and CRC diagnosis were found to be inversely correlated with the number of Y176C alleles (p=0.003 &p<0.001, respectively, linear regression). Analysis of mortality and cancer risk in 350 obligate MUTYH mutation heterozygote parents of European MAP patients revealed they were at a two fold increased risk of CRC compared with the general population. To investigate whether germline mutations in other base excision repair or DNA damage protection genes predispose to colorectal adenomas, the ORFs of 7DG, MPG, SMUG1, MBD4, APE1, POLL and NUDT5vtere sequenced in a cohort of 58 unrelated patients with multiple (>10) colorectal adenomas in whom APC or biallelic MUTYH mutations had not been demonstrated. No clearly pathogenic mutations were identified, suggesting that defects in these glycosylases are not frequently associated with colorectal polyposis