title: Characterization of mutator pathway in younger-age-onset colorectal adenocarcinomas.
abstract: The high-frequency microsatellite instability (MSI-H) phenotype, frequently identified in hereditary nonpolyposis colorectal cancer (HNPCC), also accounts for approximately 15% of sporadic colorectal cancers. Microsatellite instability (MSI) occurs from the mutational inactivation of the DNA mismatch repair genes, i.e. hMSH2 and hMLH1 in HNPCC, as well as from epigenetic inactivation of hMLH1 in sporadic colorectal tumors. The mutator pathway including microsatellite instability, hMLH1 promoter methylation, and hMSH2 and hMLH1 mutation patterns were identified in 21 sporadic colorectal adenocarcinoma patients younger than 30 yr excluding HNPCC. More than half of tumors showed MSI, with five MSI-H and six MSI-L (low-frequency microsatellite instability). Three of six MSI-H tumors showed the hMLH1 promoter methylation and did not express the hMLH1 protein. On the other hand, all MSI-L and all MSS (microsatellite stable) tumors expressed both hMSH2 and hMLH1 proteins. Two novel mutations, i.e. a missense mutation in hMLH1 and a splice-site alteration in hMSH2, were identified in two patients respectively. Although mutator pathway was implicated in younger-age-onset colorectal carcinogenesis, many tumors appeared to evolve from different genetic events other than hMSH2 and hMLH1 mutations frequently identified in HNPCC.
authors.affiliation: Department of Surgery and Pathology, University of Ulsan College of Medicine and Asan Institute for Life sciences, Seoul, Korea.
authors.forename: Seon Ae
authors.initials: SA
authors.lastname: Roh
authors.forename: Hee Cheol
authors.initials: HC
authors.lastname: Kim
authors.forename: Jung Seon
authors.initials: JS
authors.lastname: Kim
authors.forename: Jin Cheon
authors.initials: JC
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D012042:Registries
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein