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Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

Abstract

Depending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair (MMR) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts. The main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes. We found six rearrangements in the MSH2 gene (five deletions and dup5-6), and one aberration in the MLH1 gene (del5-6).  More>>
Authors:
Zavodna, Katarina; Krivulcik, Tomas; Bujalkova, Maria Gerykova; [1]  Slamka, Tomas; Martinicky, David; Ilencikova, Denisa; [2]  Bartosova, Zdena [1] 
  1. Laboratory of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava (Slovakia)
  2. National Cancer Institute, Department of Oncologic Genetics, Klenova 1, 833 01 Bratislava (Slovakia)
Publication Date:
Nov 20, 2009
Product Type:
Journal Article
Resource Relation:
Journal Name: BMC Cancer (Online); Journal Volume: 9; Other Information: PMCID: PMC2788582; PUBLISHER-ID: 1471-2407-9-405; PMID: 19930554; OAI: oai:pubmedcentral.nih.gov:2788582; Copyright (c)2009 Zavodna et al; licensee BioMed Central Ltd.; This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0) (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.; Country of input: International Atomic Energy Agency (IAEA)
Subject:
60 APPLIED LIFE SCIENCES; 62 RADIOLOGY AND NUCLEAR MEDICINE; CARRIERS; DNA SEQUENCING; GENES; LOSSES; MUTATIONS; NEOPLASMS; PATIENTS; POPULATIONS; PROBES; SCREENING
OSTI ID:
22387474
Country of Origin:
United Kingdom
Language:
English
Other Identifying Numbers:
Journal ID: ISSN 1471-2407; TRN: GB15$3167093083
Availability:
Available from http://dx.doi.org/10.1186/1471-2407-9-405; Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788582
Submitting Site:
INIS
Size:
page(s) 405
Announcement Date:
Oct 22, 2015

Citation Formats

Zavodna, Katarina, Krivulcik, Tomas, Bujalkova, Maria Gerykova, Slamka, Tomas, Martinicky, David, Ilencikova, Denisa, and Bartosova, Zdena. Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers. United Kingdom: N. p., 2009. Web. doi:10.1186/1471-2407-9-405.
Zavodna, Katarina, Krivulcik, Tomas, Bujalkova, Maria Gerykova, Slamka, Tomas, Martinicky, David, Ilencikova, Denisa, & Bartosova, Zdena. Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers. United Kingdom. doi:10.1186/1471-2407-9-405.
Zavodna, Katarina, Krivulcik, Tomas, Bujalkova, Maria Gerykova, Slamka, Tomas, Martinicky, David, Ilencikova, Denisa, and Bartosova, Zdena. 2009. "Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers." United Kingdom. doi:10.1186/1471-2407-9-405. https://www.osti.gov/servlets/purl/10.1186/1471-2407-9-405.
@misc{etde_22387474,
title = {Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers}
author = {Zavodna, Katarina, Krivulcik, Tomas, Bujalkova, Maria Gerykova, Slamka, Tomas, Martinicky, David, Ilencikova, Denisa, and Bartosova, Zdena}
abstractNote = {Depending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair (MMR) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts. The main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes. We found six rearrangements in the MSH2 gene (five deletions and dup5-6), and one aberration in the MLH1 gene (del5-6). The MSH2 deletions were of three types (del1, del1-3, del1-7). We detected LOH at the LGR region in the single MLH1 case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region. LGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1 or MSH2 gene (heterozygous LGR region, SNP, or microsatellite) is a novel finding and can be regarded as a partial LOH. The conversion begins within the gene, and the details of conversion tracts are discussed for each case.}
doi = {10.1186/1471-2407-9-405}
journal = {BMC Cancer (Online)}
volume = {9}
journal type = {AC}
place = {United Kingdom}
year = {2009}
month = {Nov}
}