Novel MLH1 and MSH2 germline mutations in the first HNPCC families identified in Slovakia.
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.
Bartosova
Zdena
Z
Laboratory of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, Bratislava, Slovakia. exonbar@savba.sk
Fridrichova
Ivana
I
Bujalkova
Maria
M
Wolf
Brigitte
B
Ilencikova
Denisa
D
Krizan
Peter
P
Hlavcak
Peter
P
Palaj
Julius
J
Lukac
Ludovit
L
Lukacova
Margita
M
Böör
Andrej
A
Haider
Ritva
R
Jiricny
Josef
J
Nyström-Lahti
Minna
M
Marra
Giancarlo
G
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
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