title: APC mutations in colorectal tumors with mismatch repair deficiency.
abstract: We have investigated the influence of genetic instability [replication error (RER) phenotype] on APC (adenomatous polyposis coli), a gene thought to initiate colorectal tumorigenesis. The prevalence of APC mutations was similar in RER and non-RER tumors, indicating that both tumor types share this step in neoplastic transformation. However, in a total of 101 sequenced mutations, we noted a substantial excess of APC frameshift mutations in the RER cases (70% in RER tumors versus 47% in non-RER tumors, P < 0.04). These frameshifts were characteristic of mutations arising in cells deficient in DNA mismatch repair, with a predilection for mononucleotide repeats in the RER tumors (P < 0.0002), particularly (A)n tracts (P < 0.00007). These findings suggest that the genetic instability that is reflected by the RER phenotype precedes, and is responsible for, APC mutation in RER large bowel tumors and have important implications for understanding the very earliest stages of neoplasia in patients with tumors deficient in mismatch repair.
authors.affiliation: University of Edinburgh, Department of Surgery, Royal Infirmary, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: N
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: A J
authors.initials: AJ
authors.lastname: McKinley
authors.forename: S M
authors.initials: SM
authors.lastname: Farrington
authors.forename: L J
authors.initials: LJ
authors.lastname: Curtis
authors.forename: A H
authors.initials: AH
authors.lastname: Wyllie
authors.forename: S
authors.initials: S
authors.lastname: Zheng
authors.forename: J K
authors.initials: JK
authors.lastname: Willson
authors.forename: S D
authors.initials: SD
authors.lastname: Markowitz
authors.forename: P
authors.initials: P
authors.lastname: Morin
authors.forename: K W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: B
authors.initials: B
authors.lastname: Vogelstein
authors.forename: M G
authors.initials: MG
authors.lastname: Dunlop
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000209:etiology / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004260:DNA Repair; D004261:DNA Replication; D004276:DNA, Satellite; D016368:Frameshift Mutation; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D016296:Mutagenesis
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D003598:Cytoskeletal Proteins; D004276:DNA, Satellite