title: Frameshift mutations at coding mononucleotide repeats of the hRAD50 gene in gastrointestinal carcinomas with microsatellite instability.
abstract: Microsatellite instability (MSI) and frameshift mutations in genes containing nucleotide repeats have been reported in a subset of colorectal and gastric carcinomas. This study describes the analysis of MSI-positive colorectal (39 cases) and gastric carcinomas (36 cases) for the presence of frameshift mutations of the six genes known to be involved in DNA repair and containing mononucleotide repeats in their coding region. Our mutational study of the 75 MSI-positive tumors revealed frequent mutations in hRAD50 (23 cases, 31%), BLM (16 cases, 21%), and hMSH6 (16 cases, 21%); rare mutations in BRCA1 (1 case, 1%) and ATM (3 cases, 4%); and no mutation in NBS1. In contrast, no frameshift mutation was found in 60 MSI-negative colorectal and gastric carcinomas. The mutation of hRAD50, a gene that is involved in the response to cellular DNA damage and forms a complex with hMRE11 and NBS1, has not been reported previously. Our results suggest that frameshift mutations of hRAD50, BLM, and hMSH6 are selected and play a role in the tumorigenesis of colorectal and gastric carcinomas with MSI. The MSI targeting of the hRAD50 and BLM genes represents an additional link between MSI and DNA repair because alteration of these genes could accelerate defective DNA repair.
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: N G
authors.initials: NG
authors.lastname: Kim
authors.forename: Y R
authors.initials: YR
authors.lastname: Choi
authors.forename: M J
authors.initials: MJ
authors.lastname: Baek
authors.forename: Y H
authors.initials: YH
authors.lastname: Kim
authors.forename: H
authors.initials: H
authors.lastname: Kang
authors.forename: N K
authors.initials: NK
authors.lastname: Kim
authors.forename: J S
authors.initials: JS
authors.lastname: Min
authors.forename: H
authors.initials: H
authors.lastname: Kim
mesh_terms: D017766:Acid Anhydride Hydrolases; D000230:Adenocarcinoma / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D015179:Colorectal Neoplasms / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics*; D016368:Frameshift Mutation; D019398:Genes, BRCA1 / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D053484:RecQ Helicases; D013274:Stomach Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases; D045643:DNA Repair Enzymes