title: Somatic mutations in mismatch repair genes in sporadic gastric carcinomas are not a cause but a consequence of the mutator phenotype.
abstract: In hereditary nonpolyposis colorectal cancer (HNPCC), patients' mismatch repair (MMR) gene mutations cause MMR deficiency, leading to microsatellite instability (MSI-H). MSI-H is also found in a substantial fraction of sporadic gastric carcinomas (SGC), mainly due to MLH1 promoter hypermethylation, although somatic mutations in MMR genes have been described. We aimed to investigate which MMR defects are present in SGC. Twenty-nine MSI-H SGC investigated previously for MLH1 promoter hypermethylation were screened for somatic mutations in MLH1, MSH2, MSH6, MLH3, and MBD4 by denaturing gradient gel electrophoresis and sequencing. Five truncating mutations (three in MSH6, one in MLH3, and one in MBD4) and one missense mutation (MLH1) were identified. Of these, three truncating mutations were in MSI-H cases that lack MLH1 hypermethylation. As all truncating mutations were found in the coding poly-A tracts, it seems likely that they result from the MSI phenotype rather than cause it. In summary, somatic mutations in MMR genes are rare in SGC and do not explain the development of these tumors reflecting, rather than causing, the mutator phenotype. Other MMR genes are probably involved in MSI-H gastric cancer without MLH1 hypermethylation.
authors.affiliation: IPATIMUP- Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Roberto Frias, 4200-465 Porto, Portugal. mafaldap@hotmail.com
authors.forename: Mafalda
authors.initials: M
authors.lastname: Pinto
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Rob G J
authors.initials: RG
authors.lastname: Mensink
authors.forename: Luís
authors.initials: L
authors.lastname: Cirnes
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D004706:Endodeoxyribonucleases / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C403623:MLH3 protein, human; D009687:Nuclear Proteins; D004706:Endodeoxyribonucleases; C118712:MBD4 protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein