Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas

• Published in: Gynecologic oncology Vol. 137; no. 2; pp. 306 - 310
• Main Authors: McConechy, M.K, Talhouk, A, Li-Chang, H.H, Leung, S, Huntsman, D.G, Gilks, C.B, McAlpine, J.N
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2015
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adenosine Triphosphatases - genetics; Biomarkers, Tumor - genetics; Cohort Studies; DNA Mismatch Repair; DNA Repair Enzymes - genetics; DNA-Binding Proteins - genetics; Endometrial cancer; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Female; Hematology, Oncology and Palliative Medicine; Humans; Immunohistochemistry; Lynch syndrome; Microsatellite Instability; Middle Aged; Mismatch repair; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein - genetics; Nuclear Proteins - genetics; Obstetrics and Gynecology; Phenotype; Microsatellite instability; Endometrial cancer; Mismatch repair; Lynch syndrome
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2015.01.541

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%. Discussion 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.