title: Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression.
abstract: OBJECTIVE
  The relationship between germ-line mutations of hMSH2 and hMLH1, microsatellite instability (MSI), and loss of DNA mismatch repair (MMR) gene expression were studied to formulate an effective selection protocol for patients with suspected hereditary nonpolyposis colorectal cancer who should be offered genetic testing.
  
  
  METHODS
  Patients eligible for germ-line analysis of hMLH1 and hMSH2 were selected. Tumor specimens were obtained to assess MSI and loss of MMR gene expression.
  
  
  RESULTS
  Among 37 patients who participated in the study, two hMSH2 and two hMLH1 missense mutations (11%) were detected, none of which was found in a panel of 60 healthy volunteers. High MSI was found in five tumors (19%) and low MSI in 10 tumors (39%); 12 tumors (46%) were microsatellite stable. Four tumors demonstrated loss of hMLH1, and three tumors demonstrated loss of hMSH2 protein expression.
  
  
  CONCLUSIONS
  No relationship was found between MMR gene mutations and MSI; low or no MSI was found in the four patients with germ-line mutations, and none of the five patients with high MSI demonstrated abnormalities of MMR genes. On the contrary, loss of hMLH1 or hMSH2 expression was found in the tumors from three of the four patients demonstrating germ-line mutations. These data suggest that germ-line mutations of the MMR gene can occur in people with MSI-negative tumors. Sensitive clinical criteria and the study of MMR gene expression may be useful to identify this subset of patients.
authors.affiliation: Department of Clinica di Oncologia Medica, University of Ancona, Ancona, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Scartozzi
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchi
authors.forename: Saverio
authors.initials: S
authors.lastname: Rosati
authors.forename: Eva
authors.initials: E
authors.lastname: Galizia
authors.forename: Annalisa
authors.initials: A
authors.lastname: Antolini
authors.forename: Cristian
authors.initials: C
authors.lastname: Loretelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Piga
authors.forename: Italo
authors.initials: I
authors.lastname: Bearzi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cellerino
authors.forename: Emilio
authors.initials: E
authors.lastname: Porfiri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; 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