GERMLINE MUTATIONS IN THE 3'-PART OF APC EXON-15 DO NOT RESULT IN TRUNCATED PROTEINS AND ARE ASSOCIATED WITH ATTENUATED ADENOMATOUS POLYPOSIS-COLI

Familial adenomatous polyposis (FAP) is an inherited predisposition to colorectal cancer characterized by the development of numerous adenom atous polyps predominantly in the colorectal region. Germline mutation s in the adenomatous polyposis coli (APC) gene are responsible for mos t cases of FAP, Mutations at the 5' end of APC are known to be associa ted with a relatively mild form of the disease, called attenuated aden omatous polyposis coli (AAPC), We identified a frameshift mutation in the 3' part of exon 15, resulting in a stop codon at 1862, in a large Dutch kindred with AAPC. Western blot analysis of lymphoblastoid cell lines derived from affected family members from this kindred, as well as from a previously reported Swiss family carrying a frameshift mutat ion at codon 1987 and displaying a similar attenuated phenotype, showe d only the wild-type APC protein. Our study indicates that chain-termi nating mutations located in the 3' part of APC do not result in detect able truncated polypeptides and we hypothesize that this is likely to be the basis for the observed AAPC phenotype.