title: Novel MLH1 and MSH2 germline mutations in the first HNPCC families identified in Slovakia.
abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly-inherited cancer predisposition syndrome, in which the susceptibility to cancer of the colon, endometrium and ovary is linked to germline mutations in DNA mismatch repair (MMR) genes. We have recently initiated a cancer prevention program in suspected HNPCC families in the Slovak Republic. The first ten families fulfilling Amsterdam criteria or Bethesda guidelines were screened for germline mutations in MLH1 and MSH2, two MMR genes most frequently mutated in HNPCC families. Six mutations were identified, five of which have not been reported previously. Two of the three new mutations in MLH1 (c.380+2T>A; c.307-2A>C) were absent from 100 chromosomes of healthy controls and probably cause a splicing defect, while the third was a 1 bp deletion (c.1261delA). In the MSH2 gene, one new nonsense (c.1030C>T [p.Q344X]) and one missense (c.524T>C [p.L175P]) mutation were identified. This latter variant was not found in 104 alleles of healthy control individuals. Moreover, a previously-reported pathogenic mutation (c.677G>T [p.R226L]) was found in one kindred. The clinical data and the genotypic and phenotypic evaluation of the tumors indicate that all the new alterations are pathogenic HNPCC mutations.
authors.affiliation: Laboratory of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, Bratislava, Slovakia. exonbar@savba.sk
authors.forename: Zdena
authors.initials: Z
authors.lastname: Bartosova
authors.forename: Ivana
authors.initials: I
authors.lastname: Fridrichova
authors.forename: Maria
authors.initials: M
authors.lastname: Bujalkova
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wolf
authors.forename: Denisa
authors.initials: D
authors.lastname: Ilencikova
authors.forename: Peter
authors.initials: P
authors.lastname: Krizan
authors.forename: Peter
authors.initials: P
authors.lastname: Hlavcak
authors.forename: Julius
authors.initials: J
authors.lastname: Palaj
authors.forename: Ludovit
authors.initials: L
authors.lastname: Lukac
authors.forename: Margita
authors.initials: M
authors.lastname: Lukacova
authors.forename: Andrej
authors.initials: A
authors.lastname: Böör
authors.forename: Ritva
authors.initials: R
authors.lastname: Haider
authors.forename: Josef
authors.initials: J
authors.lastname: Jiricny
authors.forename: Minna
authors.initials: M
authors.lastname: Nyström-Lahti
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D017668:Age of Onset; D000368:Aged; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000209:etiology / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; 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; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D018154:Slovakia / Q000453:epidemiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein