Inherited colorectal polyposis and cancer risk of the APC I1307K polymorphism

Germ-line and somatic truncating mutations of the APC gene are thought to i nitiate colorectal tumor formation in familial adenomatous polyposis syndro me and sporadic colorectal carcinogenesis, respectively, Recently, an isole ucine-->lysine polymorphism at codon 1307 (I1307K) of the APC gene has been identified in 6%-7% of the Ashkenazi Jewish population. To assess the risk of this common APC allelic variant in colorectal carcinogenesis, we have a nalyzed a large cohort of unselected Ashkenazi Jewish subjects with adenoma tous polyps and or colorectal cancer, for the APC I1307K polymorphism. The APC I1307K allele was identified in 48 (10.1%) of 476 patients. Compared wi th the frequency in two separate population control groups, the APC I1307K allele is associated with an estimated relative risk of 1.5-1.7 for colorec tal neoplasia (both P = .01). Furthermore, compared with noncarriers, APC I 1307K carriers had increased numbers of adenomas and colorectal cancers per patient (P = .03), as well as a younger age at diagnosis. We conclude that the APC I1307K variant leads to increased adenoma formation and directly c ontributes to 3%-4% of all Ashkenazi Jewish colorectal cancer. The estimate d relative risk for carriers may justify specific clinical screening for th e 360,000 Americans expected to harbor this allele, and genetic testing in the setting of long-term-outcome studies may impact significantly on colore ctal cancer prevention in this population.