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Myelodysplastic Syndrome

Molecular patterns in cytopenia patients with or without evidence of myeloid neoplasm—a comparison of 756 cases

Leukemia volume 32, pages 2295–2298 (2018)Cite this article

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Molecular genetic analyses play numerous roles for workup in myeloid malignancies. Mutated genes define entities (e.g., NPM1, CEBPA, or RUNX1 mutated AML (acute myeloid leukemia) [1]) or prognostic patient subgroups (e.g., SF3B1 mutations are associated with ring sideroblasts and a favorable prognosis in MDS) (myelodysplastic syndrome) [2,3,4]. Analysis of large AML or MDS cohorts revealed that not only single mutations, but rather patterns of genetic aberrations are highly important regarding diagnosis and classification but also to understand disease biology and clinical outcome [5, 6]. Recently, interpreting clonality itself has emerged as a novel challenge for genetic analysis. One mutation in multiple cells suggests that all cells have outgrown from one ancestor. If clonality is detected in individuals without symptoms, it is categorized as clonal hematopoiesis of indeterminate potential [7]. Clonality in patients with cytopenia is defined as clonal cytopenia of undetermined significance (CCUS) [8]. CCUS patients are at increased risk of progression to MDS or secondary AML [9]. The initial clone expands and acquires novel genetic aberrations during progression [7, 10]. However, testing for clonality has not yet been implemented as a standard diagnostic procedure. Therefore, little is known about the frequency of CCUS or the genetic patterns of CCUS compared to MDS or AML in a routine setting.

Panel sequencing allows analyzing multiple genes and is a clinically applicable approach to identify molecular patterns for AML and MDS patients. We extended this approach to cytopenia patients in whom no definite morphological diagnosis based on bone marrow smears could be made. Our aim was to identify the frequency of clonality (mutations), further subdivide this group by morphology, if possible, and compare genetic patterns to patients with proven AML and MDS. We included 756 patients (Table S1) with cytopenia, who were referred to our laboratory between July 2016 and September 2017. Patients gave written informed consent with genetic analysis and research studies in accordance with the Declaration of Helsinki. The scientific analysis and evaluation of the samples has been approved by the ethics committee of the Bavarian Physicians' Chamber. We included 208 proven de novo AML and 154 MDS patient (including 15 MDS-U with cytogenetic aberrations according to WHO [1], Table S2). Chromosome banding analysis was performed according to standard protocols [11]. In addition, we included cytopenia patients (n = 394), who did not fulfill definite criteria for AML or MDS by morphology or cytogenetic analysis (normal karyotype: n = 332, non MDS-defining aberrations: n = 56; possibly constitutional aberrations: n = 6). Samples were further characterized depending on cytomorphology as “MDS possible” (n = 71), “MDS not visible,” (n = 94) “unclear” (n = 40), and “reactive” condition (n = 189). A detailed description of the cytomorphological classification is given as supplement.

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References

  1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  CAS  PubMed  Google Scholar 

  2. Malcovati L, Hellstrom-Lindberg E, Bowen D, Ades L, Cermak J, Del Canizo MC, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122:2943–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;365:1384–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bejar R, Papaemmanuil E, Haferlach T, Garcia-Manero G, Maciejewski JP, Sekeres MA. et al. Somatic mutations in MDS patients are associated with clinical features and predict prognosis independent of the IPSS-R: analysis of combined datasets from the international working group for prognosis in MDS-Molecular Committee. Clinically Relevant Abstract. Blood (ASH Annual Meeting Abstract). 2015;126:907.

  5. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Makishima H, Yoshizato T, Yoshida K, Sekeres MA, Radivoyevitch T, Suzuki H, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet. 2017;49:204–12.

    Article  CAS  PubMed  Google Scholar 

  7. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bejar R. CHIP, ICUS, CCUS and other four-letter words. Leukemia. 2017;31:1869–71.

    Article  CAS  PubMed  Google Scholar 

  9. Malcovati L, Galli A, Travaglino E, Ambaglio I, Rizzo E, Molteni E, et al. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood. 2017;129:3371–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer. 2016;17:5–19.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Schoch C, Schnittger S, Bursch S, Gerstner D, Hochhaus A, Berger U, et al. Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases. Leukemia. 2002;16:53–59.

    Article  CAS  PubMed  Google Scholar 

  12. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.

    Article  PubMed  Google Scholar 

  13. Kwok B, Hall JM, Witte JS, Xu Y, Reddy P, Lin K, et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood. 2015;126:2355–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, 81377, Munich, Germany

    Constance Baer, Christian Pohlkamp, Claudia Haferlach, Wolfgang Kern & Torsten Haferlach

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  1. Constance Baer
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Correspondence to Constance Baer.

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C.B. and C.P.: employment by MLL Munich Leukemia Laboratory; C.H., W.K., and T.H.: equity ownership of MLL Munich Leukemia Laboratory.

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Baer, C., Pohlkamp, C., Haferlach, C. et al. Molecular patterns in cytopenia patients with or without evidence of myeloid neoplasm—a comparison of 756 cases. Leukemia 32, 2295–2298 (2018). https://doi.org/10.1038/s41375-018-0119-8

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