title: Mutational analysis of hMsh6 in Israeli HNPCC and HNPCC-like families.
abstract: Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly hMlh1 and hMsh2, underlie Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Germline hMSH6 gene mutations have been reported in a small subset of HNPCC families. In the present study, ethnically diverse individuals with HNPCC and HNPCC-like features were genotyped for hMsh6 germline mutations using exon-specific PCR, DGGE, and DNA sequencing. The study encompassed 92 individuals representing 88 unrelated families who were previously analyzed for Msh2 and Mlh1 mutations: Jewish Ashkenazim (n = 44), non-Ashkenazim (n = 27), Israeli Moslem-Arab (n = 15), Druze (n=3), and Cypriot non-Jews (n = 3). Of the study population, 71 had colon cancer (CRC), mean age at diagnosis was 50.9+/-13.2 years (range 16-73 years), 5 had endometrial cancer (two with concurrent CRC), (mean 43.6+/-3.26 years, range 38-45 years), and unaffected individuals (n = 18) were first degree relatives within HNPCC families and were genotyped at a mean age of 48.3+/-11.7 years (range 30-69 years). Of the 92 individuals analyzed, none showed a truncating hMsh6 mutation, and 6 (6.6%) harbored one of three germline missense mutations: a previously reported one (V878A), and two novel mutations (V509A, S227I). The pathogenic significance of these three missense mutations is yet unclear. In addition, 5 polymorphisms were detected, 2 of which were novel. We conclude that the rate of pathogenic hMsh6 mutations in HNPCC families of Jewish and Mediterranean origin is low, and that mutations in other genes probably account for the phenotype in these families.
authors.affiliation: Head of the Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Genetics, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel.
authors.forename: Shiri
authors.initials: S
authors.lastname: Dovrat
authors.forename: Arie
authors.initials: A
authors.lastname: Figer
authors.forename: Herma H
authors.initials: HH
authors.lastname: Fidder
authors.forename: Pavlos
authors.initials: P
authors.lastname: Neophytou
authors.forename: Zvi
authors.initials: Z
authors.lastname: Fireman
authors.forename: Ravit
authors.initials: R
authors.lastname: Geva
authors.forename: Jamal
authors.initials: J
authors.lastname: Zidan
authors.forename: Dov
authors.initials: D
authors.lastname: Flex
authors.forename: Shimon Bar
authors.initials: SB
authors.lastname: Meir
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
mesh_terms: D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D015180:Electrophoresis, Gel, Two-Dimensional; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007557:Israel; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D016133:Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein