title: Semiquantitative assessment of immunohistochemistry for mismatch repair proteins in Lynch syndrome.
abstract: OBJECTIVE
  To assess semiquantitative immunohistochemistry as used in the diagnosis of Lynch syndrome.
  
  
  RESULTS
  Tumour sections from 51 mutation carriers and 17 controls were stained with antibodies against MLH1, MSH2, MSH6 and PMS2. Intensity of immunoreactivity and percentage positivity were recorded on scales of 0-3 and 0-4, respectively. These scores were multiplied for a score of 0-12 per slide. Receiver-operator characteristic (ROC) curves of staining performance for the identification of mutation carriers were evaluated, and optimum cut-offs calculated. The area under the MLH1 ROC curve was 0.981 [95% confidence interval (CI) 0.952, 1.000]. The area under the MSH2 ROC curve was 0.899 (95% CI 0.796, 1.000). For MLH1 staining, a score<or=4 gives a sensitivity of 100.0% (95% CI 84.0, 100.0) and a specificity of 91.5% (95% CI 79.6, 97.6) for identifying MLH1 mutation carriers. For MSH2 staining, a score<or=4 gives a sensitivity of 87.5% (95% CI 61.7, 98.4) and specificity of 88.5% (95% CI 76.5, 95.6) for identifying MSH2 mutation carriers.
  
  
  CONCLUSIONS
  This study supports a semiquantitative slide assessment method. Protein expression may occur in the context of known pathogenic mutations, a potential pitfall in the screening process.
authors.affiliation: Department of General Surgery, Manchester Royal Infirmary, Manchester, M13 9WL, UK. emma.barrow@doctors.org.uk
authors.forename: Emma
authors.initials: E
authors.lastname: Barrow
authors.forename: Emma
authors.initials: E
authors.lastname: Jagger
authors.forename: Judith
authors.initials: J
authors.lastname: Brierley
authors.forename: Andrew
authors.initials: A
authors.lastname: Wallace
authors.forename: Gareth
authors.initials: G
authors.lastname: Evans
authors.forename: James
authors.initials: J
authors.lastname: Hill
authors.forename: Ray
authors.initials: R
authors.lastname: McMahon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000096:biosynthesis* / Q000235:genetics; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D012372:ROC Curve; D012680:Sensitivity and Specificity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes