title: Ten novel MSH2 and MLH1 germline mutations in families with HNPCC.
abstract: 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.
authors.affiliation: Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Dresden University of Technology, Dresden, Germany. Stefan.Krueger@mailbox.tu-dresden.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Krüger
authors.forename: Andrea
authors.initials: A
authors.lastname: Bier
authors.forename: Jens
authors.initials: J
authors.lastname: Plaschke
authors.forename: Ruth
authors.initials: R
authors.lastname: Höhl
authors.forename: Daniela E
authors.initials: DE
authors.lastname: Aust
authors.forename: Friedmar R
authors.initials: FR
authors.lastname: Kreuz
authors.forename: Steffen R
authors.initials: SR
authors.lastname: Pistorius
authors.forename: Hans D
authors.initials: HD
authors.lastname: Saeger
authors.forename: Veit
authors.initials: V
authors.lastname: Rothhammer
authors.forename: Oliver
authors.initials: O
authors.lastname: Al-Taie
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000483:Alleles; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D018389:Codon, Nonsense; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D018095:Germ-Line Mutation; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D022821:RNA Splice Sites; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein