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Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome
  1. Monika Morak1,2,
  2. Udo Koehler2,
  3. Hans Konrad Schackert3,
  4. Verena Steinke4,
  5. Brigitte Royer-Pokora5,
  6. Karsten Schulmann6,
  7. Matthias Kloor7,
  8. Wilhelm Höchter8,
  9. Josef Weingart8,
  10. Cortina Keiling2,
  11. Trisari Massdorf1,
  12. Elke Holinski-Feder1,2,
  13. the German HNPCC consortium
  1. 1Medical Department, Campus Innenstadt, Klinikum der Universität, Munich, Germany
  2. 2MGZ–Center of Medical Genetics, Munich, Germany
  3. 3Department of Surgical Research, Technische Universität Dresden, Dresden, Germany
  4. 4Institute of Human Genetics, University of Bonn, Bonn, Germany
  5. 5Institute of Human Genetics, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
  6. 6Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
  7. 7Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
  8. 8Gastroenterology Office, Munich, Germany
  1. Correspondence to Professor Dr Elke Holinski-Feder, MGZ–Center of Medical Genetics, Bayerstr 3–5, 80335 Munich, Germany; elkeholinski-feder{at}


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.

  • Lynch syndrome
  • gene rearrangement
  • hereditary colorectal cancer
  • sequence inversion
  • cancer: colon
  • microarray
  • epigenetics
  • molecular genetics

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  • Funding This work was supported by the Wilhelm-Sander Foundation and the German Cancer Aid (Deutsche Krebshife).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Local ethics committees of all university hospitals involved in the study approved the study protocol.

  • Provenance and peer review Not commissioned; externally peer reviewed.