title: Somatic instability of the APC I1307K allele in colorectal neoplasia.
abstract: 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 approximately 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)8 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.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Surgery, The University of Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Gryfe
authors.forename: N
authors.initials: N
authors.lastname: Di Nicola
authors.forename: S
authors.initials: S
authors.lastname: Gallinger
authors.forename: M
authors.initials: M
authors.lastname: Redston
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000483:Alleles; D015179:Colorectal Neoplasms / Q000208:ethnology / Q000235:genetics*; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D017491:Genes, APC / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D007585:Jews / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*