title: Identification of concurrent germ-line mutations in hMSH2 and/or hMLH1 in Japanese hereditary nonpolyposis colorectal cancer kindreds.
abstract: We analyzed microsatellite instability, alterations of the polyadenine tract in TGF-beta RII (transforming growth factor beta type II receptor gene), and mutations of hMSH2 and hMLH1 in 32 patients with familial colorectal cancer (29 kindreds) fulfilling the clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), defined at the 34th Annual Meeting of Japanese Society for Cancer of the Colon and Rectum (Tokushima, Japan, 1991), including five kindreds fulfilling the Amsterdam criteria. Eighteen of 32 (56%) cases were replication error positive (RER+) at two or more microsatellite loci analyzed. The clinicopathological characteristics of RER+ cases corresponded well with those reported previously. Eleven of 18 RER+ cases showed RER+ at most of the microsatellite loci examined. Among these 11 cases (10 kindreds), 3 kindreds fulfilled the Amsterdam criteria and 7 kindreds did not. For these 10 kindreds, germ-line mutations in hMSH2 and hMLH1 were detected for 6 kindreds by PCR-SSCP analysis and direct sequencing. Only two of these six fulfilled the Amsterdam criteria; more than one germ-line mutation was detected in hMSH2 and/or hMLH1. Specifically, two point mutations of hMSH2 were detected in two kindreds, one point mutation of both hMSH2 and hMLH1 was detected in one kindred, two point mutations of hMSH2 and one point mutation of hMLH1 were detected in one kindred, and two point mutations of hMLH1 and one point mutation of hMSH2 were detected in one kindred. In addition, 19 of 26 (74%) cancer lesions of these 11 cases with the RER phenotype showed alterations of the polyadenine tract in TGF-beta RII. From our data, although seven kindreds did not fulfill the Amsterdam criteria, we considered them as HNPCC. Therefore, we suggest that the "Japanese criteria" have the advantage of being able to detect more HNPCC kindreds from borderline HNPCC kindreds.
authors.affiliation: First Department of Pathology, Hiroshima University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakahara
authors.forename: H
authors.initials: H
authors.lastname: Yokozaki
authors.forename: W
authors.initials: W
authors.lastname: Yasui
authors.forename: K
authors.initials: K
authors.lastname: Dohi
authors.forename: E
authors.initials: E
authors.lastname: Tahara
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D018095:Germ-Line Mutation; D006801:Humans; D007564:Japan; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010375:Pedigree; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005819:Genetic Markers; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein