THE APC VARIANTS I1307K AND E1317Q ARE ASSOCIATED WITH COLORECTAL TUMORS, BUT NOT ALWAYS WITH A FAMILY HISTORY

Classical familial adenomatous polyposis (FAP) is a high-penetrance au tosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mut ations in the APC gene. A variant of FAP is attenuated adenomatous pol yposis coli, which results from germ-line mutations in the 5' and 3' r egions of the APC gene. Attenuated adenomatous polyposis coli patients have ''multiple'' colorectal adenomas (typically fewer than 100) with out the florid phenotype of classical FAP. Another group of patients w ith multiple adenomas has no mutations in the APC gene, and their phen otype probably results from variation at a locus, or loci, elsewhere i n the genome. Recently, however, a missense variant of APC (I1307K) wa s described that confers an increased risk of colorectal tumors, inclu ding multiple adenomas, in Ashkenazim. We have studied a set of 164 pa tients with multiple colorectal adenomas and/or carcinoma and analyzed codons 1263-1377 (exon 15G) of the APC gene for germ-line variants. T hree patients with the I1307K allele were detected, each of Ashkenazi descent. Four patients had a germ-line E1317Q missense variant of APC that was not present in controls; one of these individuals had an unus ually large number of metaplastic polyps of the colorectum. There is i ncreasing evidence that there exist germ-line variants of the APC gene that predispose to the development of multiple colorectal adenomas an d carcinoma, but without the florid phenotype of classical FAP, and po ssibly with importance for colorectal cancer risk in the general popul ation.