title: Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical Department, Campus Innenstadt, Klinikum der Universität, Munich, Germany; MGZ-Center of Medical Genetics, Munich, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Morak
authors.forename: Udo
authors.initials: U
authors.lastname: Koehler
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Schackert
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.forename: Brigitte
authors.initials: B
authors.lastname: Royer-Pokora
authors.forename: Karsten
authors.initials: K
authors.lastname: Schulmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Höchter
authors.forename: Josef
authors.initials: J
authors.lastname: Weingart
authors.forename: Cortina
authors.initials: C
authors.lastname: Keiling
authors.forename: Trisari
authors.initials: T
authors.lastname: Massdorf
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D001483:Base Sequence; D007446:Chromosome Inversion / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005190:Family; D005260:Female; D020440:Gene Duplication / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics*; D005820:Genetic Testing; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018076:DNA, Complementary; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1