title: Screening for defective DNA mismatch repair in stage II and III colorectal cancer patients.
abstract: OBJECTIVE
  Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome usually present in younger patients, show loss of mismatch repair (MMR) gene expression, and exhibit microsatellite instability (MSI). About 12% of sporadic colorectal cancers also show MMR loss and MSI. The aims of this study were to evaluate MMR loss and MSI in relation to patient age, sex, tumor stage, and site in the large bowel.
  
  
  METHODS
  Tissue microarrays were created from 1020 stage II and III colorectal cancer cases and immunohistochemical staining performed to detect expression of the 2 major MMR proteins, hMLH1 and hMSH2. MSI was determined using the BAT-26 mononucleotide repeat.
  
  
  RESULTS
  Ten percent of tumors showed loss of hMLH1 expression and 1.2% showed loss of hMSH2 expression. hMLH1 loss was more frequent in women (P < .001), older patients (P = .004), earlier stage tumors (P = .0001), and proximal colon tumors ( P < .0001). In contrast, tumors showing hMSH2 loss were more frequent in younger (P < .001), male (P = .05) patients and were distributed evenly between the proximal colon and distal colon/rectum. Eleven percent of tumors were MSI+ and these showed similar age, sex, stage, and site characteristics as tumors with hMLH1 loss. Discordance between MMR loss and MSI+ was found in 24 of 983 (2.4%) tumors. Of the 231 patients aged <60 years at diagnosis, 12 (5.2%) showed loss of hMLH1 and 8 (3.5%) showed loss of hMSH2.
  
  
  CONCLUSIONS
  Routine immunohistochemical screening for MMR loss in younger colorectal cancer patients may provide a useful, first-step screening tool for the population-based detection of HNPCC.
authors.affiliation: School of Surgery and Pathology, University of Western Australia, Nedlands, Australia.
authors.forename: Siaw Ming
authors.initials: SM
authors.lastname: Chai
authors.forename: Nik
authors.initials: N
authors.lastname: Zeps
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Shearwood
authors.forename: Fabienne
authors.initials: F
authors.lastname: Grieu
authors.forename: Adrian
authors.initials: A
authors.lastname: Charles
authors.forename: Jennet
authors.initials: J
authors.lastname: Harvey
authors.forename: Jack
authors.initials: J
authors.lastname: Goldblatt
authors.forename: David
authors.initials: D
authors.lastname: Joseph
authors.forename: Barry
authors.initials: B
authors.lastname: Iacopetta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch / Q000235:genetics*; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein