The adenomatous polyposis coli (APC) gene is proposed to function as a gatekeeper of colorectal neoplasia. A germ-line variant of this gene, the APC I1307K allele, is present in ∼6% of the Ashkenazi Jewish population. To assess the role in tumorigenesis of the variant (A)8 tract produced by this allele, we undertook a somatic mutation analysis of the region surrounding codon 1307 in colorectal tumors from APC I1307K carriers. Somatic mutations involving the variant (A)3 tract were identified in 53 of 127 (42%) tumors from APC I1307K carriers compared with 5 of 127 (4%) mutations involving the wild-type allele of these tumors (P < 0.0001). Loss of heterozygosity of the wild-type allele was significantly more common in tumors with APC I1307K allele mutations (25 of 41, 61%) compared with APC I1307K carrier tumors without mutation of the variant (A)8 tract (12 of 53, 23%; P < 0.0005). This somatic biallelic APC inactivation further confirms the biological importance of the I1307K germ-line variant. The vast majority of APC I1307K somatic mutations consisted of a single adenine insertion (insA) involving the variant (A)8 tract. This insA mutation was mutually exclusive of the presence of microsatellite instability with 0 of 49 tumors with insA displaying BAT-26 instability compared with 9 of 78 tumors without insA (P = 0.01). These findings support a model where somatic instability of the (A)8 tract produced by the APC I1307K allele leads to increased APC gene inactivation and directly accounts for 42% of the colorectal neoplasms occurring in APC I1307K carriers.
This research was supported in part by the National Cancer Institute of Canada (to S. G. and M. R.) with funds provided by the Canadian Cancer Society. R. G. is a Terry Fox Research Fellow of the National Cancer Institute of Canada with funds provided by the Canadian Cancer Society.