Genetic and molecular analysis of a variant form of adenomatous polyposis coli

Adenomatous polyposis coli (APC) are responsible for an inherited predisposition to colorectal cancer through development of multiple adenomatous polyps. The subject of my doctoral thesis has been the study of genetic variant of APC, called attenuated APC (AAPC), in which carriers of mutant APC allele develop fewer adenomatous polyps and exhibit a later age of colon-cancer onset than "classical" APC patients. Dr. Mark Leppert mapped the disease phenotype in a large Utah pedigree, the first AAPC family recognized. Subsequently, four other families were ascertained in which the phenotypic pattern was different from classical polyposis but similar to that of the "prototype" AAPC kindred. By multilocus linkage analysis, I mapped the mutant phenotype to the APC locus on human chromosome 5q. To more accurately determine the carrier status of AAPC family members at risk for developing the disorder, an effort was undertaken to obtain a highly polymorphic marker close to the APC gene. I identified a CA-repeat "microsatellite" locus 30-70 Kb from APV that revealed at least 13 different alleles in the general population. I use this DNA marker to perform linkage analysis in affected families, and obtained large increases in statistical significance over previously available markers. The new maker was especially helpful for presymptomatic diagnosis of APC carriers in families requesting genotypic analysis through the DNA Diagnostics Laboratory at the University of Utah. I searched for mutations in the APC gene in the AAPC families in the hope of revealing the molecular basis for those with classical polyposis. Two distinct germline mutations were identified in APC among our five AAPC families. Tow of our collaborators in Paris, Sylviane Olschwang and Gillies Thomas, identified two additional mutations in to French AAPC families. All four distinct AAPC mutation predicted truncation product, either single base-pair changes or frameshifts, and they were similar in nature to mutations in families with classical APC. However, they differed in that all four mutations were located very close to one another and very near the 5' end of the gene.