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      Molecular/Cytogenetic Education for Hematopathology Fellows

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          Abstract

          Objectives

          At a discussion on molecular/cytogenetic education for hematopathology fellows at the 2018 Society for Hematopathology Program Directors Meeting, consensus was that fellows should understand basic principles and indications for and limitations of molecular/cytogenetic testing used in routine practice. Fellows should also be adept at integrating results of such testing for rendering a final diagnosis. To aid these consensus goals, representatives from the Society for Hematopathology and the Association for Molecular Pathology formed a working group to devise a molecular/cytogenetic curriculum for hematopathology fellow education.

          Curriculum Summary

          The curriculum includes a primer on cytogenetics and molecular techniques. The bulk of the curriculum reviews the molecular pathology of individual malignant hematologic disorders, with applicable molecular/cytogenetic testing for each and following the 2017 World Health Organization classification of hematologic neoplasms. Benign hematologic disorders and bone marrow failure syndromes are also discussed briefly. Extensive tables are used to summarize genetics of individual disorders and appropriate methodologies.

          Conclusions

          This curriculum provides an overview of the current understanding of the molecular biology of hematologic disorders and appropriate ancillary testing for their evaluation. The curriculum may be used by program directors for training hematopathology fellows or by practicing hematopathologists.

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          Most cited references95

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          Clinical effect of point mutations in myelodysplastic syndromes.

          Rafael Bejar, Kristen Stevenson, Omar Abdel-Wahab … (2011)
          Myelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems. We used a combination of genomic approaches, including next-generation sequencing and mass spectrometry-based genotyping, to identify mutations in samples of bone marrow aspirate from 439 patients with myelodysplastic syndromes. We then examined whether the mutation status for each gene was associated with clinical variables, including specific cytopenias, the proportion of blasts, and overall survival. We identified somatic mutations in 18 genes, including two, ETV6 and GNAS, that have not been reported to be mutated in patients with myelodysplastic syndromes. A total of 51% of all patients had at least one point mutation, including 52% of the patients with normal cytogenetics. Mutations in RUNX1, TP53, and NRAS were most strongly associated with severe thrombocytopenia (P<0.001 for all comparisons) and an increased proportion of bone marrow blasts (P<0.006 for all comparisons). In a multivariable Cox regression model, the presence of mutations in five genes retained independent prognostic significance: TP53 (hazard ratio for death from any cause, 2.48; 95% confidence interval [CI], 1.60 to 3.84), EZH2 (hazard ratio, 2.13; 95% CI, 1.36 to 3.33), ETV6 (hazard ratio, 2.04; 95% CI, 1.08 to 3.86), RUNX1 (hazard ratio, 1.47; 95% CI, 1.01 to 2.15), and ASXL1 (hazard ratio, 1.38; 95% CI, 1.00 to 1.89). Somatic point mutations are common in myelodysplastic syndromes and are associated with specific clinical features. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors. (Funded by the National Institutes of Health and others.).
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            Acute myeloid leukemia ontogeny is defined by distinct somatic mutations.

            R Coleman Lindsley, Brenton Mar, Emanuele Mazzola … (2015)
            Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637.
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              Clonal architecture of secondary acute myeloid leukemia.

              Matthew J. Walter, Dong Shen, Li Ding … (2012)
              The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood. We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations. Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene. Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.).
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                Author and article information

                Contributors
                Journal
                Title: American Journal of Clinical Pathology
                Publisher: Oxford University Press (OUP)
                ISSN (Print): 0002-9173
                ISSN (Electronic): 1943-7722
                Publication date Created: August 2020
                Publication date Created: July 07 2020
                Publication date Created: May 23 2020
                Publication date Other: August 2020
                Publication date (Print): July 07 2020
                Publication date (Electronic): May 23 2020
                Volume: 154
                Issue: 2
                Pages: 149-177
                Affiliations
                [1 ]Department of Pathology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH (Society for Hematopathology Representative)
                [2 ]Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (Association for Molecular Pathology Representative)
                [3 ]Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
                [4 ]Department of Pathology, Boston Children’s Hospital, Boston, MA
                [5 ]Department of Pathology, University of Washington, and Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA
                [6 ]Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora
                Article
                DOI: 10.1093/ajcp/aqaa038
                SO-VID: 829971d3-3dd6-4e83-94d7-c42bfb1f0987
                Copyright © © 2020
                License:

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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