Microsatellite Instability Assessment by Immunohistochemistry in Acute Myeloid Leukemia: A Reappraisal and Review of the Literature |
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| Affiliation: | 1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;2. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;3. Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan;1. Department of Internal Medicine, Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa, Iowa City, IA;2. Department of Biostatics, University of Nebraska Medical Center, Omaha, NE;3. Department of Internal Medicine, Rochester General Hospital, Rochester, NY;4. Nobel College, Pokhara University, Kathmandu, Nepal;5. Department of Internal Medicine, Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha, NE;6. Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE;7. Department of Internal Medicine, Section of Hematology, Yale University School of Medicine and Yale Cancer Center, New Haven, CT;8. Department of Medicine, Division of Hematology/Oncology, University of Rochester Medical Center, Rochester, NY;9. Division of Geriatrics, Gerontology and Palliative Medicine, University of Nebraska Medical Center, Omaha, NE;1. Departments of Pathology and Lab Medicines, H. L. Moffitt Cancer Center and Research Institute, Tampa, FL;2. Department of Malignant Hematology, H. L. Moffitt Cancer Center and Research Institute, Tampa, FL;3. Department of Bone Marrow Transplantation, H. L. Moffitt Cancer Center and Research Institute, Tampa, FL;1. Unit of Functional Oncogenomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via F. Gallini 2, 33081 Aviano, Italy;2. Department of Pathology, Circolo Hospital ASST Settelaghi, via O. Rossi 9, 21100, Varese, Italy;3. Research Center for the Study of Hereditary and Familial Tumors, Department of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy;4. Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, The Royal Institute of Technology KTH, Tomtebodavägen 23B, 171 65 Solna, Stockholm, Sweden;5. Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Via Zucchi, 18 - 20095 Cusano Milanino (MI);6. Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Vanvitelli 32, 20133 Milan, Italy;7. IGA Technology Services Srl, Via J. Linussio, 51, 33100 Udine, Italy;8. U.O. Gastroenterologia ed Endoscopia Digestiva, Ospedale S. Chiara, APSS, Via A. de Gasperi 79 – 38123, Trento, Italy;1. Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt;2. Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt;3. Pediatric Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt;4. Biostatistics and Cancer Epidemiology Department, National Cancer Institute, Cairo University, Cairo, Egypt;1. Department of Integrative Biology, School of Bio Sciences and Technology, VIT, Vellore, Tamil Nadu, India;2. Department of Biomedical Sciences, College of Health and Sciences, Qatar University, Doha, Qatar |
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| Abstract: | BackgroundMicrosatellite instability (MSI) is caused by defects in DNA mismatch repair (MMR) components. Inactivation of any MMR gene(s), including hMLH1, hMSH2, hMSH6, and hPMS2, can result in MSI. Immunohistochemistry (IHC) is a sensitive and specific screening tool for MSI that can detect loss of expression of one or more MMR components. Of the four MMR markers, hMLH1 and hMSH2 are considered most informative of MSI status. There has been renewed interest in MSI status in view of its favorable association with response to immune checkpoint inhibitors in some cancers. MMR expression patterns in acute myeloid leukemia (AML) have not been evaluated systematically.MethodsWe used clinically-validated IHC assays to assess the expression of hMLH1, hMSH2, hMSH6, and/or hPMS2 in formalin-fixed paraffin-embedded tissue sections of bone marrow core biopsies from patients diagnosed with AML. Mutation profiling was performed using next-generation sequencing to assess for mutations in MMR genes.ResultsThe study group included 236 patients with AML, including a cohort treated on a clinical trial of azacitidine and nivolumab (NCT02397720). In addition, hMSH6, and/or hPMS2 expression was assessed in 99 AML patients with diploid karyotype. All patients, except two, had retained expression of all MMR markers assessed: One patient from the azacytidine+nivolumab group had zonal patchy loss of staining of hMLH1 and, to a lesser extent, a similar staining pattern of hMSH2; and one patient from the AML with diploid karyotype group had loss of hMSH2 but retained expression of hMLH1, hMSH6 and hPMS2. In addition, a retrospective analysis on a separate cohort of 139 patients with primary AML, on which next generation sequencing profiling was performed, identified 14 cases with alterations in MMR genes.Conclusion and remarksMMR loss is a rare event in AML, thus does not appear to underlie response patterns to anti-PD1 therapy. |
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| Keywords: | Immunohistochemistry Bone marrow |
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