title: Seven novel MLH1 and MSH2 germline mutations in hereditary nonpolyposis colorectal cancer.
abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent hereditary form of colorectal cancer and is caused by germline mutations in mismatch repair (MMR) genes. The majority of mutations occur in MLH1 and MSH2. We report hereby seven novel germline mutations in these two genes (five in MLH1 and two in MSH2). All mutations have been found in families fulfilling criteria of the Bethesda guidelines and four of which also fulfilled the Amsterdam criteria. We identified three insertions or deletions of 1 bp leading to premature stop codons (MLH1: c.341delC, c.1413-1414insA; MSH2: c.1119delG) and three nonsense mutations (MLH1: c.67G>T [E23X], c.436C>T [Q146X]; MSH2: c.1857T>G [Y619X]). The corresponding tumors showed a high level of microsatellite instability (MSI-H) and a complete loss of expression of the affected protein. In addition, a missense mutation in MLH1 was identified (c.1984A>C [T662P]). The respective tumor also showed a high level of microsatellite instability but a reduced, rather then lost, expression of the MLH1-protein. This missense mutation was not found in 107 healthy control individuals and in 54 HNPCC patients.
authors.affiliation: Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, University of Technology, Dresden, Germany. Stefan.Krueger@mailbox.tu-dresden.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Krüger
authors.forename: Jens
authors.initials: J
authors.lastname: Plaschke
authors.forename: Steffen
authors.initials: S
authors.lastname: Pistorius
authors.forename: Birgit
authors.initials: B
authors.lastname: Jeske
authors.forename: Stephan
authors.initials: S
authors.lastname: Haas
authors.forename: Heike
authors.initials: H
authors.lastname: Krämer
authors.forename: Irene
authors.initials: I
authors.lastname: Hinterseher
authors.forename: Andrea
authors.initials: A
authors.lastname: Bier
authors.forename: Friedmar R
authors.initials: FR
authors.lastname: Kreuz
authors.forename: Franz
authors.initials: F
authors.lastname: Theissig
authors.forename: Hans D
authors.initials: HD
authors.lastname: Saeger
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000556:secondary; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D009852:Omentum / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein