Nontruncating APC germ-line mutations and mismatch repair deficiency play a minor role in APC mutation-negative polyposis

Familial adenomatous polyposis, an autosomal-dominantly inherited colorecta l cancer predisposition syndrome, is caused by germ-line mutations in the a denomatous polyposis coli (APC) gene. Despite the use of different screenin g methods, studies worldwide fail to identify, APC mutations in 20-50% of a ll familial adenomatous polyposis patients (APC mutation-negatives). In thi s study, missense mutations in the coding region of the APC gene, which wou ld have been missed by the protein truncation test, as well as mutations in the APC promoter and the 3' untranslated region, were determined by the si ngle nucleotide polymorphism discovery assay and direct DNA sequencing in 3 1 mutation-negative polyposis patients. Seventeen gene alterations were ide ntified, whereof four (12.9%) represent possibly pathogenic germ-line mutat ions: silent A290T (promoter) and A8822G (3' untranslated region) as well a s missense R99W and E1317Q (coding region). The 27 remaining, truly APC mut ation-negative polyposis patients displayed a significantly later age at di agnosis compared with APC mutation carriers (46.1 versus 35.2 years; P < 0. 01). APC mutation-negative individuals with > 100 colonic polyps were more likely to present with extracolonic disease (P < 0.05) than those with < 10 0. Assessment of microsatellite instability (NISI), a hallmark of mismatch repair deficiency, in 68 tumors from 21 truly APC mutation-negative patient s, identified 4 (5.9%) unstable tubulo-villous adenomas (3 NISI-High and I MSI-Low), stemming from 4 (19%) unrelated individuals and likely to be caus ed by, hMLHI promoter hypermethylation. In conclusion, only a small proport ion of APC germ-line mutation carriers is missed by the protein truncation test, and mismatch repair deficiency does not seem to substantially contrib ute to tumor development in APC mutation-negative polyposis patients.