THE GENETIC BACKGROUND OF FAMILIAL ADENOMATOUS POLYPOSIS - LINKAGE ANALYSIS, THE APC GENE IDENTIFICATION AND MUTATION SCREENING

Familial adenomatous polyposis (FAP) is an autosomal, dominantly inher ited disease that predisposes to colorectal cancer and is characterize d by the presence of hundreds to thousands of adenomas covering the co lon and rectum. Mapping of the FAP locus to 5q2I-q22 by linkage studie s in families ultimately allowed the identification of the APC (Adenom atous Polyposis Coli) gene itself. The APC gene comprises 15 exons wit h a 9 kilobase RNA transcript and a 312 kilodalton final protein produ ct. This discovery transformed the diagnosis of FAP and offered direct identification of defective gene carriers by mutation screening. Curr ently used techniques have been successful in detecting mutations in 1 5 to 67 percent of patients. To date, at least 136 different mutations have been described in 301 unrelated FAP patients, most of which (98% ) are translation terminating mutations leading to a truncated final p rotein product. Promising applications or development of novel procedu res, like the protein truncation test (PTT), are under way for the rem aining FAP patients. With the exception of the description of a critic al boundary in exon 9 for the presence or absence of CHRPE, there are no clear genotype-phenotype relationships, but mutations located in th e 5' half of exon 15 seem to lead to a more severe phenotype. Very lit tle is know about the APC protein product function. The APC protein co uld be involved in cell-to-cell signalling and/or cell adhesion functi ons. The APC gene is a tumour suppressor gene involved in early stages of sporadic colorectal carcinogenesis. Further understanding of the A PC gene function may define a rational approach for early dectection, prevention strategies, assessment of prognosis and treatment of colore ctal cancer. In this regard, animal models of FAP like the MIN (Multip le Intestinal Neoplasia) mouse or the APC 1638 mouse, are promising an d powerful tools.