title: Spectrum of germ-line MLH1 and MSH2 mutations in Austrian patients with hereditary nonpolyposis colorectal cancer.
abstract: BACKGROUND
  Germ-line mutations in mismatch repair genes are associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, which is characterized by susceptibility to cancer of the colon, endometrium, small bowel or urothelium at an unusually young age and with a high degree of penetration in all generations.
  
  
  METHODS
  One hundred and nine individuals from 46 Austrian families who fulfilled the Amsterdam criteria (n = 29) or at least one of the Bethesda guidelines (n = 17) were analyzed for mutations in MLH1 and MSH2. Microsatellite instability was determined in the tumors of index persons and affected relatives.
  
  
  CONCLUSIONS
  High-grade instability was present in 60.6% of the tumor samples from index patients. Twenty-three germ-line DNA sequence variants in 24/46 families and four somatic mutations in three tumors were detected in MLH1 and MSH2. Fifteen mutations are novel. None of the newly identified germ-line variants was found in 100 alleles of healthy control individuals. We were able to characterize two intronic variants (MLH1 c.589-10T>A; MSH2 c.367-1G>A) with regard to their effect on mRNA. Both created new splice sites that replaced the regular ones. Germ-line mutations occurred in 44.8% of the families fulfilling the Amsterdam criteria and in 35.3% of the Bethesda patients. The detection of a pathogenic mutation was strongly correlated with microsatellite instability in the tumor DNA (p=0.007). This study is the first comprehensive report of mutations in mismatch repair genes in Austrian patients with HNPCC.
authors.affiliation: Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wolf
authors.forename: Silvia
authors.initials: S
authors.lastname: Henglmueller
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Janschek
authors.forename: Denisa
authors.initials: D
authors.lastname: Ilencikova
authors.forename: Carmen
authors.initials: C
authors.lastname: Ludwig-Papst
authors.forename: Michael
authors.initials: M
authors.lastname: Bergmann
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
authors.forename: Friedrich
authors.initials: F
authors.lastname: Wrba
authors.forename: Judith
authors.initials: J
authors.lastname: Karner-Hanusch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001317:Austria; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D003627:Data Interpretation, Statistical; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA
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; D012333:RNA, Messenger; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein