title: Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas.
abstract: BACKGROUND
  A proportion of endometrial carcinomas (ECs) are associated with deficient DNA mismatch repair (MMR). These tumors are characterized by high levels of microsatellite instability (MSI). Identification of MSI is important in identifying women who should be tested for Lynch syndrome and identifying a phenotype that may have specific prognostic and predictive implications. Genomic characterization of ECs has shown that MSI tumors form a distinct subgroup. The two most common methodologies for MSI assessment have not been compared in EC.
  
  
  METHODS
  Pentaplex mono and di-nucleotide PCR for MSI testing was compared to MMR IHC (presence/absence of MLH1, MSH2, MSH6, PMS2) in a cohort of patients with EC. Concordance, Kappa statistic, sensitivity, specificity, positive and negative predictive values were obtained on the cross-tabulation of results.
  
  
  RESULTS
  Comparison of both MSI and MMR status was complete for 89 cases. Overall agreement between methods (concordance) was 93.3% (95% CI[85.9%-97.5%]). A one-sided test to determine whether the accuracy is better than the "no information rate," which is taken to be the largest class percentage in the data, is significant (p<0.00001). Unweighted Kappa was 0.84, along with the sensitivity (88.5%), specificity (95.2%), PPV (88.5%), and NPV (95.2%). The balanced accuracy (i.e. the average between sensitivity and specificity) was 92%.
  
  
  CONCLUSIONS
  We show the equivalence of MSI testing and MMR IHC. We advocate the implementation of MMR IHC in future EC classification schemes, enabling stratification of cases for future clinical trials as well as assisting identification of Lynch syndrome, so that screening and risk reducing interventions can be undertaken.
authors: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.
authors: M K
authors: MK
authors: McConechy
authors: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.
authors: A
authors: A
authors: Talhouk
authors: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.
authors: H H
authors: HH
authors: Li-Chang
authors: Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.
authors: S
authors: S
authors: Leung
authors: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.
authors: D G
authors: DG
authors: Huntsman
authors: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.
authors: C B
authors: CB
authors: Gilks
authors: Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, University of British Columbia, 2775 Laurel St. 6th Floor, Vancouver V5Z 1M9, BC, Canada. Electronic address: jessica.mcalpine@vch.ca.
authors: J N
authors: JN
authors: McAlpine
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D015331:Cohort Studies; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype
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
keywords: Endometrial cancer; Lynch syndrome; Microsatellite instability; Mismatch repair