SOMATIC INSTABILITY OF THE APC 11307K ALLELE IN COLORECTAL NEOPLASIA

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 similar to 6% of the Ashkenazi J ewish population, To assess the role in tumorigenesis of the variant ( A)(8) tract produced by this allele, we undertook a somatic mutation a nalysis of the region surrounding codon 1307 in colorectal tumors from APC I1307K carriers. Somatic mutations involving the variant (A)(8) t ract were identified in 53 of 127 (42%) tumors from APC I1307K carrier s 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 wit hout mutation of the variant (A)(8) tract (12 of 53; 23%; P < 0.0005). This somatic biallelic APC inactivation further confirms the biologic al importance of the I1307K germ-line variant. The vast majority of AP C I1307K somatic mutations consisted of a single adenine insertion (in sA) involving the variant (A)(8) tract. This insA mutation was mutuall y 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 s omatic instability of the (A)(8) tract produced by the APC I1307K alle le leads to increased APC gene inactivation and directly accounts for 42% of the colorectal neoplasms occurring in APC I1307K carriers.