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Neoplasma Vol.53, p.269-276, 2006 |
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Title: Novel and recurrent germline alterations in the MLH1 and MSH2 genes identified in hereditary nonpolyposis colorectal cancer patients in Slovakia | ||
Author: K., ZAVODNA ; M., BUJALKOVA ; T., KRIVULCIK ; A., ALEMAYEHU ; M., SKORVAGA ; G., MARRA ; I., FRIDRICHOVA ; J., JIRICNY ; Z., BARTOSOVA ; | ||
Abstract: Hereditary non-polyposis colorectal cancer (HNPCC) is associated
with germline mutations in DNA mismatch repair
genes, predominantly MSH2 and MLH1. Mutation carriers develop
cancers in the colorectum, endometrium, ovary, stomach,
small intestine and the upper urinary tract. We describe here the
results of a mutational analysis of 11 unrelated HNPCC
patients by direct genomic sequencing of MLH1 and MSH2. The
alterations found include 7 novel changes and 4 different
pathogenic mutations described previously in Poland, Moldavia,
Finland, Germany, France and USA. Four novel pathogenic
mutations in the MLH1 gene include two frameshift mutations
(c.1150delG and c.1210_1211delCT), one missense
mutation (c.793C>A) and one intron-exon border mutation (c.546-
2A>C). The last change resulted in the skipping of exon
7, as shown by sequencing of RT-PCR products. The only novel MSH2
pathogenic change was a nonsense mutation
c.1129C>T. The novel intronic change c.381-41A>G in MLH1 was found
in a patient carrying a previously-described mutation
in the MSH2 gene. Interestingly, two unrelated patients carried
also a novel change in the promoter region of MLH1 in
one of the CpG islands (c.-269C>G). However, this alteration does
not abrogate transcription, as shown by RT-PCR analysis.
In summary, most (~80%) pathogenic germline mutations detected in
the studied group of patients by direct genomic sequencing
of MLH1 and MSH2 were located in the MLH1 gene. These and previous
data indicate that the majority of
germline point mutations and small deletions/insertions in HNPCC
families in Slovakia affect the MLH1 locus.
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Keywords: HNPCC, germline mutations, MSH2, MLH1 | ||
Year: 2006, Volume: 53, Issue: | Page From: 269, Page To: 276 | |
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