title: Genetic linkage analysis in hereditary non-polyposis colon cancer syndrome.
abstract: Hereditary Non-polyposis Colon Cancer Syndrome (HNPCC) is the most common cause of familial colorectal cancer. Molecular genetic studies of HNPCC have shown evidence of locus heterogeneity, and mutations in four genes (hMSH2, hMLH1, hPMS1, and hPMS2) which encode components of the mismatch enzyme repair system may cause HNPCC. To determine the extent and nature of locus heterogeneity in HNPCC, we performed genetic linkage studies in 14 HNPCC families from eastern and north-western England. Linkage to hMLH1 was excluded in six families, each of which were likely to be linked to hMSH2 (lod score > 1.0 in each family and total lod score for all six families = 7.64). Linkage to hMSH2 was excluded in three families, each of which were likely to be linked to hMLH1 (lod score > 1.0 in each family and total lod score at hMLH1 for all three families = 3.93). In the remaining five families linkage to hMSH2 or hMLH1 could not be excluded. These results confirm locus heterogeneity in HNPCC and suggest that, in the population studied, most large families with HNPCC will have mutations in hMSH2 or hMLH1. We did not detect any correlation between clinical phenotype and the genetic linkage results, but a Muir-Torre syndrome family excluded from linkage to hMLH1 was likely to be linked to hMSH2 and showed microsatellite instability in a tumour from an affected relative.
authors.affiliation: Cambridge University Department of Pathology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Froggatt
authors.forename: J
authors.initials: J
authors.lastname: Koch
authors.forename: R
authors.initials: R
authors.lastname: Davies
authors.forename: D G
authors.initials: DG
authors.lastname: Evans
authors.forename: A
authors.initials: A
authors.lastname: Clamp
authors.forename: O W
authors.initials: OW
authors.lastname: Quarrell
authors.forename: J
authors.initials: J
authors.lastname: Weissenbach
authors.forename: S V
authors.initials: SV
authors.lastname: Hodgson
authors.forename: B A
authors.initials: BA
authors.lastname: Ponder
authors.forename: D E
authors.initials: DE
authors.lastname: Barton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D000328:Adult; D002352:Carrier Proteins; D002874:Chromosome Mapping; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004739:England; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D010375:Pedigree; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D011518:Proto-Oncogene Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes