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Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome

Background A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ∼10-15% of cases of suspec...

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Main Authors: Morak, Monika (Author) , Koehler, Udo (Author) , Schackert, Hans Konrad (Author) , Steinke, Verena (Author) , Royer-Pokora, Brigitte (Author) , Schulmann, Karsten (Author) , Kloor, Matthias (Author) , Höchter, Wilhelm (Author) , Weingart, Josef (Author) , Keiling, Cortina (Author) , Massdorf, Trisari (Author) , Holinski-Feder, Elke (Author)
Corporate Author: German Hereditary Nonpolyposis Colorectal Cancer Study Group (Author)
Format: Article (Journal)
Language:English
Published: 28 June 2011
In: Journal of medical genetics
Year: 2011, Volume: 48, Issue: 8, Pages: 513-519
ISSN:1468-6244
DOI:10.1136/jmedgenet-2011-100050
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/jmedgenet-2011-100050
Verlag, lizenzpflichtig, Volltext: https://jmg.bmj.com/content/48/8/513
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Author Notes:Monika Morak, Udo Koehler, Hans Konrad Schackert, Verena Steinke, Brigitte Royer-Pokora, Karsten Schulmann, Matthias Kloor, Wilhelm Höchter, Josef Weingart, Cortina Keiling, Trisari Massdorf, Elke Holinski-Feder, the German HNPCC Consortium
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Summary:Background A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ∼10-15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected. - Methods Oligo array analysis was performed to search for genomic imbalances in patients with suspected mutation-negative Lynch syndrome with MLH1 deficiency in their colorectal tumours. - Results and conclusion A deletion in the LRRFIP2 (leucine-rich repeat flightless-interacting protein 2) gene flanking the MLH1 gene was detected, which turned out to be a paracentric inversion on chromosome 3p22.2 creating two new stable fusion transcripts between MLH1 and LRRFIP2. A single-nucleotide polymorphism in MLH1 exon 8 was expressed from both alleles, initially pointing to appropriate MLH1 function at least in peripheral cells. In a second case, an inherited duplication of the MLH1 gene region resulted in constitutional MLH1 promoter methylation. Constitutional MLH1 promoter methylation may therefore in rare cases be a heritable disease mechanism and should not be overlooked in seemingly sporadic patients.
Item Description:Gesehen am 07.09.2022
Physical Description:Online Resource
ISSN:1468-6244
DOI:10.1136/jmedgenet-2011-100050

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