title: The APC Variant p.Glu1317Gln predisposes to colorectal adenomas by a novel mechanism of relaxing the target for tumorigenic somatic APC mutations.
abstract: Multiple rare nonsynonymous variants in APC predispose to colorectal adenomas. The mechanisms through which such variants act have been unclear, but it has been proposed that a specific ("just-right") level of beta-catenin signaling is required for colorectal tumorigenesis. This appears to be mediated by selection for APC genotypes that retain one, or rarely two, 20 amino acid beta-catenin downregulating repeats (20AARs). We investigated the mechanism through which the variant p.Glu1317Gln (c.3949G>C) contributes to colorectal tumorigenesis. We compared the patterns of somatic APC mutations in tumors from patients with attenuated familial adenomatous polyposis (AFAP) who did, or did not, coinherit p.Glu1317Gln with their AFAP-causing APC mutations. Only 8.2% (4/49) of tumors carrying p.Glu1317Gln had somatic mutations predicted to result in mutant polypeptides retaining a single 20AAR, compared to 62.1% (36/58) of those which did not carry this variant (P=5.64 x 10(-9)). Furthermore, tumors with p.Glu1317Gln often carried somatic mutations that were unusually early or late (downstream of the second 20AAR) in the APC open reading frame. These data support a novel mechanism in which p.Glu1317Gln in combination with other weak mutant APC alleles (generating polypepetides with zero, two, or three 20AARs) can provide the necessary growth advantage for colorectal tumorigenesis.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Dallosso
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Duncan
authors.initials: D
authors.lastname: Azzopardi
authors.forename: Valentina
authors.initials: V
authors.lastname: Moskvina
authors.forename: Nada
authors.initials: N
authors.lastname: Al-Tassan
authors.forename: Geraint T
authors.initials: GT
authors.lastname: Williams
authors.forename: Shelley
authors.initials: S
authors.lastname: Idziaszczyk
authors.forename: D Rhodri
authors.initials: DR
authors.lastname: Davies
authors.forename: Peter
authors.initials: P
authors.lastname: Milewski
authors.forename: Sally
authors.initials: S
authors.lastname: Williams
authors.forename: John
authors.initials: J
authors.lastname: Beynon
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
mesh_terms: D000236:Adenoma / Q000235:genetics*; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D016133:Polymerase Chain Reaction
chemical_list: D017931:DNA Primers