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      The Genomics of Myelodysplastic Syndromes: Origins of Disease Evolution, Biological Pathways, and Prognostic Implications

      review-article
      Author(s): 1 , 2 , 1 , *
      Publication date (Electronic):
      Journal: Cells
      Publisher: MDPI
      Keywords: MDS, mutations, deregulated expression

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          Abstract

          The molecular pathogenesis of myelodysplastic syndrome (MDS) is complex due to the high rate of genomic heterogeneity. Significant advances have been made in the last decade which elucidated the landscape of molecular alterations (cytogenetic abnormalities, gene mutations) in MDS. Seminal experimental studies have clarified the role of diverse gene mutations in the context of disease phenotypes, but the lack of faithful murine models and/or cell lines spontaneously carrying certain gene mutations have hampered the knowledge on how and why specific pathways are associated with MDS pathogenesis. Here, we summarize the genomics of MDS and provide an overview on the deregulation of pathways and the latest molecular targeted therapeutics.

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          The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

          Daniel Arber, Attilio Orazi, Robert P. Hasserjian … (2016)
          The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here.
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            Age-related clonal hematopoiesis associated with adverse outcomes.

            Siddhartha Jaiswal, Pierre Fontanillas, Jason Flannick … (2014)
            The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).
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              Revised international prognostic scoring system for myelodysplastic syndromes.

              Peter Greenberg, Heinz Tuechler, Julie Schanz … (2012)
              The International Prognostic Scoring System (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.
              Article 0 comments Cited 832 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 20 November 2020
                Publication date Collection: November 2020
                Volume: 9
                Issue: 11
                Electronic Location Identifier: 2512
                Affiliations
                [1 ]Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44106, USA; awadah@ 123456ccf.org
                [2 ]Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; bithapa@ 123456mcw.edu
                Author notes
                [* ]Correspondence: visconv@ 123456ccf.org
                [†]

                These authors contributed equally.

                Article
                Publisher ID: cells-09-02512
                DOI: 10.3390/cells9112512
                PMC ID: 7699752
                PubMed ID: 33233642
                SO-VID: 1377b9e8-99bf-4703-be6f-212eb45de911
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 12 October 2020
                Date accepted : 17 November 2020
                Categories
                Subject: Review

                Keywords: mds,mutations,deregulated expression
                Data availability:
                Keywords: mds, mutations, deregulated expression

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