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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2004-9-14
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pubmed:abstractText |
Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the most common hereditary cancer-susceptibility syndromes. Germline mutations in mismatch repair genes are associated with the clinical phenotype of HNPCC. We report ten novel germline mutations, three in MSH2 and seven in MLH1. All but one mutation have been found in families fulfilling criteria of the Bethesda guidelines; four of them additionally fulfilled the Amsterdam criteria I or II. Eight mutations were considered pathogenic and predictive diagnostics in healthy family members at risk shall be undertaken; these include five frameshift mutations leading to premature stop codons, in MSH2: c.1672delT (p.S558Xfs) and c.2466_2467delTG (p.C822X) and in MLH1: c.1023delG (p.R341Xfs), c.1127_1128dupAT (p.K377Xfs) and c.1310delC (p.P437Xfs); three mutations leading to splice aberrations, in MSH2: c.1661G>C (r.1511_1661del) and in MLH1: c.677+3A>C (r.589_677del) and c.1990-2A>G predicted to result in a splice site defect. The remaining two mutations are unclassified variants with assumed pathogenicity: one missense mutation in the highly conserved ATPase domain of MLH1 (c.122A>G [p.D41G]) and one in-frame insertion of twelve nucleotides in MLH1 (c.2155_2156insATGTGTTCCACA [p.I719delinsNVFHI]). These two mutations were not found in 102 alleles of healthy control individuals. The corresponding tumors from all patients showed a high level of microsatellite instability (MSI-H). Immunohistochemistry (IHC) revealed complete loss of expression of the affected protein in the tumor cells from all but three patients. The tumors from the patients with the mutations c.1127_1128dupAT and c.1990-2A>G showed a reduction of expression of the MLH1-protein, rather than complete loss. In the tumor from the patient with the missense mutation c.122A>G [p.D41G] a normal expression of the proteins coded by MLH1 and MSH2 was noticed.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Codon, Nonsense,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/MLH1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/MSH2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/MutS Homolog 2 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/RNA Splice Sites
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1098-1004
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pubmed:author |
pubmed-author:Al-TaieOliverO,
pubmed-author:AustDaniela EDE,
pubmed-author:BierAndreaA,
pubmed-author:HöhlRuthR,
pubmed-author:KrügerStefanS,
pubmed-author:KreuzFriedmar RFR,
pubmed-author:PistoriusSteffen RSR,
pubmed-author:PlaschkeJensJ,
pubmed-author:RothhammerVeitV,
pubmed-author:SaegerHans DHD,
pubmed-author:SchackertHans KHK
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pubmed:copyrightInfo |
Copyright 2004 Wiley-Liss, Inc.
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pubmed:issnType |
Electronic
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pubmed:volume |
24
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
351-2
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:15365996-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:15365996-Adult,
pubmed-meshheading:15365996-Aged,
pubmed-meshheading:15365996-Alleles,
pubmed-meshheading:15365996-Base Pair Mismatch,
pubmed-meshheading:15365996-Carrier Proteins,
pubmed-meshheading:15365996-Codon, Nonsense,
pubmed-meshheading:15365996-Colorectal Neoplasms, Hereditary Nonpolyposis,
pubmed-meshheading:15365996-DNA-Binding Proteins,
pubmed-meshheading:15365996-Female,
pubmed-meshheading:15365996-Frameshift Mutation,
pubmed-meshheading:15365996-Germ-Line Mutation,
pubmed-meshheading:15365996-Germany,
pubmed-meshheading:15365996-Humans,
pubmed-meshheading:15365996-Male,
pubmed-meshheading:15365996-Microsatellite Repeats,
pubmed-meshheading:15365996-Middle Aged,
pubmed-meshheading:15365996-MutS Homolog 2 Protein,
pubmed-meshheading:15365996-Mutagenesis, Insertional,
pubmed-meshheading:15365996-Neoplasm Proteins,
pubmed-meshheading:15365996-Nuclear Proteins,
pubmed-meshheading:15365996-Proto-Oncogene Proteins,
pubmed-meshheading:15365996-RNA Splice Sites
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pubmed:year |
2004
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pubmed:articleTitle |
Ten novel MSH2 and MLH1 germline mutations in families with HNPCC.
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pubmed:affiliation |
Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Dresden University of Technology, Dresden, Germany. Stefan.Krueger@mailbox.tu-dresden.de
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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