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Copyright ©2007 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. May 21, 2007; 13(19): 2727-2732
Published online May 21, 2007. doi: 10.3748/wjg.v13.i19.2727
Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: Implications for genetic testing
Janos Papp, Marietta E Kovacs, Edith Olah
Janos Papp, Marietta E Kovacs, Edith Olah, Department of Molecular Genetics, National Institute of Oncology, Rath Gy. u. 7-9, H-1122 Budapest, Hungary
Author contributions: All authors contributed equally to the work.
Supported by the Hungarian Research Grants OTKA T-046570, NKFPI-00024/2005 and ETT 397/2006
Correspondence to: Dr. Edith Olah, Department Molecular Genetics, National Institute of Oncology, Rath Gy. u. 7-9, H-1122 Budapest, Hungary. e.olah@oncol.hu
Telephone: +36-1-2248788 Fax: +36-1-2248708
Received: February 2, 2007
Revised: February 21, 2007
Accepted: March 8, 2007
Published online: May 21, 2007
Abstract

AIM: To analyze the prevalence of germline MLH1 and MSH2 gene mutations and evaluate the clinical characteristics of Hungarian hereditary non-polyposis colorectal cancer (HNPCC) families.

METHODS: Thirty-six kindreds were tested for mutations using conformation sensitive gel electrophoreses, direct sequencing and also screening for genomic rearrangements applying multiplex ligation-dependent probe amplification (MLPA).

RESULTS: Eighteen germline mutations (50%) were identified, 9 in MLH1 and 9 in MSH2. Sixteen of these sequence alterations were considered pathogenic, the remaining two were non-conservative missense alterations occurring at highly conserved functional motifs. The majority of the definite pathogenic mutations (81%, 13/16) were found in families fulfilling the stringent Amsterdam I/II criteria, including three rearrangements revealed by MLPA (two in MSH2 and one in MLH1). However, in three out of sixteen HNPCC-suspected families (19%), a disease-causing alteration could be revealed. Furthermore, nine mutations described here are novel, and none of the sequence changes were found in more than one family.

CONCLUSION: Our study describes for the first time the prevalence and spectrum of germline mismatch repair gene mutations in Hungarian HNPCC and suspected-HNPCC families. The results presented here suggest that clinical selection criteria should be relaxed and detection of genomic rearrangements should be included in genetic screening in this population.

Keywords: Germline mutation; Hereditary non-polyposis colorectal cancer; MLH1; MSH2; Rearrangement