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Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas.
Gynecol Oncol. 2015 May; 137(2):306-10.GO

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.

Authors+Show Affiliations

Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver V6H 3Z6, BC, Canada.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25636458

Citation

McConechy, M K., et al. "Detection of DNA Mismatch Repair (MMR) Deficiencies By Immunohistochemistry Can Effectively Diagnose the Microsatellite Instability (MSI) Phenotype in Endometrial Carcinomas." Gynecologic Oncology, vol. 137, no. 2, 2015, pp. 306-10.
McConechy MK, Talhouk A, Li-Chang HH, et al. Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas. Gynecol Oncol. 2015;137(2):306-10.
McConechy, M. K., Talhouk, A., Li-Chang, H. H., Leung, S., Huntsman, D. G., Gilks, C. B., & McAlpine, J. N. (2015). Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas. Gynecologic Oncology, 137(2), 306-10. https://doi.org/10.1016/j.ygyno.2015.01.541
McConechy MK, et al. Detection of DNA Mismatch Repair (MMR) Deficiencies By Immunohistochemistry Can Effectively Diagnose the Microsatellite Instability (MSI) Phenotype in Endometrial Carcinomas. Gynecol Oncol. 2015;137(2):306-10. PubMed PMID: 25636458.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas. AU - McConechy,M K, AU - Talhouk,A, AU - Li-Chang,H H, AU - Leung,S, AU - Huntsman,D G, AU - Gilks,C B, AU - McAlpine,J N, Y1 - 2015/01/28/ PY - 2014/11/29/received PY - 2015/01/21/accepted PY - 2015/2/1/entrez PY - 2015/2/1/pubmed PY - 2015/8/25/medline KW - Endometrial cancer KW - Lynch syndrome KW - Microsatellite instability KW - Mismatch repair SP - 306 EP - 10 JF - Gynecologic oncology JO - Gynecol Oncol VL - 137 IS - 2 N2 - 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. SN - 1095-6859 UR - https://www.unboundmedicine.com/medline/citation/25636458/Detection_of_DNA_mismatch_repair__MMR__deficiencies_by_immunohistochemistry_can_effectively_diagnose_the_microsatellite_instability__MSI__phenotype_in_endometrial_carcinomas_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0090-8258(15)00584-3 DB - PRIME DP - Unbound Medicine ER -