PRESYMPTOMATIC DIAGNOSIS OF FAMILIAR ADENOMATOUS POLYPOSIS-COLI

Familial adenomatous polyposis (FAP), an autosomal dominant inherited disease, confers a high risk of colon cancer, and recently the gene re sponsible for FAP, termed adenomatous polyposis coli (APC) gene, was i dentified and fully characterized. PURPOSE: For the presymptomatic dia gnosis of FAP, we have performed linkage studies using two polymorphic systems close to or at the APC locus; cytosine-adenine dinucleotide r epeat length polymorphism and restriction endonuclease RsaI site poly morphism. METHODS and RESULTS: Based on the two polymorphic systems, w e have determined the haplotype at the APC locus in 23 individuals of two Korean families with FAP. From these haplotypes of individuals, we could make the diagnosis, whether affected or unaffected, in 74 perce nt of 31 at-risk persons. To decrease the chance of misdiagnosis cause d by recombinant events, the use of haplotypes was better than using o ne polymorphic system. In addition to polymorphic analysis, we have al so searched germline mutations of the APC gene in eight individuals (2 6 percent of all 31 at risk persons) of another two FAP families which could not be diagnosed definitely by linkage analysis. A 5 base-pairs deletion at codon 1309 was detected in one of the families, and a 5 b ase-pairs deletion at codon 1185 was also identified in another family by using a ribonuclease protection assay followed by DNA sequencing. From these results, we could diagnose FAP with 100 percent accuracy. C ONCLUSION: Linkage studies by the RsaI site polymorphism and cytosine- adenine repeat length polymorphism as well as the polymerase chain rea ction-based sequencing method provide accurate and efficient tools for presymptomatic diagnosis of FAP in their families.