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Genetic Testing for Familial Adenomatous Polyposis

Abstract: Familial adenomatous polyposis (FAP, Mendelian Inheritance in Man number *175100 [edited by Victor A. McKusick], accessible on line under http://www3.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?175100) is a dominantly inherited colorectal cancer predisposition syndrome. The designation Gardner Syndrome is used for phenotypic variants of FAP with additional extracolonic symptoms. After the adenomatous polyposis coli (APC) gene was identified with the help of positional cloning strategies in 1991, it became evident that inactivation of this tumor suppressor is based on loss of carboxyterminal protein‐protein interaction domains. Identification of multiple molecular constituents binding to the distal half of the APC protein revealed its crucial involvement in wnt‐signaling. Because the spectrum of mutations is predominated by small insertions and deletions, nonsense‐, and splice‐site mutations, a prescreening procedure is employed for the identification of germinal mutations in FAP patients that relies on in vitro synthesis of APC gene products, an approach also known under the acronym PTT (protein truncation test). Absence of nonsense‐mediated mRNA decay of mutated APC transcripts allows the application of a cDNA‐based coupled in vitro transcription/translation reaction for exons 1 to 14. Examination of four overlapping fragments from genomic DNA of probands reveals stops in the large APC exon 15, encompassing more than 6500 base pairs. Using this procedure, mutations causing the disease will be identified in about 80% of FAP patients. In the other cases of clinically manifest FAP, evidence exists that reduction of the steady state level of APC protein as a result of transcriptional silencing or large genomic deletions could provide for the clinical phenotype. Although some genotype‐phenotype correlations have been described, exceptions from the rule have been reported, that is, for CHRPE. Modifier genes for the development of extracolonic manifestations are currently still enigmatic. Knowledge of such genes would essentially contribute to a better presymptomatic treatment of FAP patients.