title: Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with mismatch repair deficiency.
abstract: Defects of mismatch repair are thought to be responsible for carcinogenesis in hereditary non-polyposis colorectal cancer and about 15% of sporadic colon cancers. The phenotype is seen as microsatellite instability and is known to be caused either by mutations in mismatch repair genes or by aberrant methylation of these genes stabilizing their downregulation. Lack of repair of microsatellite sequence errors, created during replication, leads to a mutation-prone phenotype. Where mutations occur within mononucleotide tracts within exons they cause translation frameshifts, premature cessation of translation and abnormal protein expression. Such mutations have been observed in the TGFbetaRII, BAX, IGFIIR, MSH3 and MSH6 genes in colon and other cancers. We describe here frameshift mutations affecting the gene for the methyl-CpG binding thymine glycosylase, MBD4, in over 40% of microsatellite unstable sporadic colon cancers. The mutations all appear heterozygous but their location would ensure truncation of the protein between the methyl-CpG binding and glycosylase domains, thus potentially generating a dominant negative effect. It is thus possible that such mutations enhance mutation frequency at other sites in these tumours. A suggestion has been made that MBD4 (MED1) mutations may lead to an increased rate of microsatellite instability but this mechanism appears unlikely due to the nature of mutations we have found.
authors.affiliation: Sir Alastair Currie CRC Laboratories, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: S
authors.initials: S
authors.lastname: Bader
authors.forename: M
authors.initials: M
authors.lastname: Walker
authors.forename: B
authors.initials: B
authors.lastname: Hendrich
authors.forename: A
authors.initials: A
authors.lastname: Bird
authors.forename: C
authors.initials: C
authors.lastname: Bird
authors.forename: M
authors.initials: M
authors.lastname: Hooper
authors.forename: A
authors.initials: A
authors.lastname: Wyllie
mesh_terms: D020137:Base Pair Mismatch; D001483:Base Sequence; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000601:surgery; D015179:Colorectal Neoplasms / Q000235:genetics; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics*; D004706:Endodeoxyribonucleases / Q000235:genetics*; D005091:Exons; D016368:Frameshift Mutation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018895:Microsatellite Repeats
chemical_list: D004706:Endodeoxyribonucleases; C118712:MBD4 protein, human