Skip to main content
SpringerLink
Log in

Recurrent Cytogenetic Abnormalities in Myelodysplastic Syndromes

  • Protocol
  • First Online:
Cancer Cytogenetics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1541))

Abstract

Cytogenetic analysis has an essential role in diagnosis, classification, and prognosis of myelodysplastic syndromes (MDS). Some cytogenetic abnormalities are sufficiently characteristic of MDS to be considered MDS defining in the appropriate clinical context. MDS with isolated del(5q) is the only molecularly defined MDS subtype. The genes responsible for many aspects of 5q- syndrome, the distinct clinical phenotype associated with this condition, have now been identified. Cytogenetics forms the cornerstone of the most widely adopted prognostic scoring systems in MDS, the international prognostic scoring system (IPSS) and the revised international prognostic scoring system (IPPS-R). Cytogenetic parameters also have utility in chronic myelomonocytic leukemia (CMML) and have been incorporated into specific prognostic scoring systems for this condition. More recently, it has been appreciated that submicroscopic copy number changes and gene mutations play a significant part in MDS pathogenesis. Integration of molecular genetics and cytogenetics holds much promise for improving clinical care and outcomes for patients with MDS.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Rollison DE, Howlader N, Smith MT et al (2008) Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood 112:45–52. doi:10.1182/blood-2008-01-134858

    Article  CAS  PubMed  Google Scholar 

  2. McQuilten ZK, Sundararajan V, Andrianopoulos N et al (2015) Monosomal karyotype predicts inferior survival independently of a complex karyotype in patients with myelodysplastic syndromes. Cancer 121:2892–2899. doi:10.1002/cncr.29396

    Article  PubMed  Google Scholar 

  3. Busque L, Paquette Y, Provost S et al (2009) Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies. Blood 113:3472–3474. doi:10.1182/blood-2008-12-195677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Genovese G, Kähler AK, Handsaker RE et al (2014) Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371:2477–2487. doi:10.1056/NEJMoa1409405

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jaiswal S, Fontanillas P, Flannick J et al (2014) Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488–2498. doi:10.1056/NEJMoa1408617

    Article  PubMed  PubMed Central  Google Scholar 

  6. Steensma DP, Bejar R, Jaiswal S et al (2015) Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126:9–16. doi:10.1182/blood-2015-03-631747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Solé F, Luño E, Sanzo C et al (2005) Identification of novel cytogenetic markers with prognostic significance in a series of 968 patients with primary myelodysplastic syndromes. Haematologica 90:1168–1178

    PubMed  Google Scholar 

  8. Haase D, Germing U, Schanz J et al (2007) New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110:4385–4395. doi:10.1182/blood-2007-03-082404

    Article  CAS  PubMed  Google Scholar 

  9. Schanz J, Tüchler H, Solè F et al (2012) New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge. J Clin Oncol 30:820–829. doi:10.1200/JCO.2011.35.6394

    Article  PubMed  PubMed Central  Google Scholar 

  10. Swerdlow SH, Campo E, Harris NL et al (eds) (2008) WHO classification of tumours of haematopoietic and lymphoid tissue. IARC, Lyon

    Google Scholar 

  11. Germing U, Lauseker M, Hildebrandt B et al (2012) Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): a multicenter study. Leukemia 26:1286–1292. doi:10.1038/leu.2011.391

    Article  CAS  PubMed  Google Scholar 

  12. Mallo M, Cervera J, Schanz J et al (2011) Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q. Leukemia 25:110–120. doi:10.1038/leu.2010.231

    Article  CAS  PubMed  Google Scholar 

  13. Arber DA, Orazi A, Hasserjian R et al (2016) The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood 127:2391–2405. doi:10.1182/blood-2016-03-643544

    Article  PubMed  Google Scholar 

  14. Ebert BL, Pretz J, Bosco J et al (2008) Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 451:335–339. doi:10.1038/nature06494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Starczynowski DT, Kuchenbauer F, Argiropoulos B et al (2010) Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med 16:49–58. doi:10.1038/nm.2054

    Article  CAS  PubMed  Google Scholar 

  16. Krönke J, Fink EC, Hollenbach PW et al (2015) Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523:183–188. doi:10.1038/nature14610

    Article  PubMed  PubMed Central  Google Scholar 

  17. Font P, Loscertales J, Benavente C et al (2013) Inter-observer variance with the diagnosis of myelodysplastic syndromes (MDS) following the 2008 WHO classification. Ann Hematol 92:19–24. doi:10.1007/s00277-012-1565-4

    Article  CAS  PubMed  Google Scholar 

  18. Smith SM, Le Beau MM, Huo D et al (2003) Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 102:43–52. doi:10.1182/blood-2002-11-3343

    Article  CAS  PubMed  Google Scholar 

  19. Quintás-Cardama A, Daver N, Kim H et al (2014) A prognostic model of therapy-related myelodysplastic syndrome for predicting survival and transformation to acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 14:401–410. doi:10.1016/j.clml.2014.03.001

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tang G, Zhang L, Fu B et al (2014) Cytogenetic risk stratification of 417 patients with chronic myelomonocytic leukemia from a single institution. Am J Hematol 89:813–818. doi:10.1002/ajh.23751

    Article  PubMed  PubMed Central  Google Scholar 

  21. Such E, Cervera J, Costa D et al (2011) Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 96:375–383. doi:10.3324/haematol.2010.030957

    Article  PubMed  Google Scholar 

  22. Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088

    CAS  PubMed  Google Scholar 

  23. Fenaux P, Mufti GJ, Hellstrom-Lindberg E et al (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10:223–232. doi:10.1016/S1470-2045(09)70003-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chun K, Hagemeijer A, Iqbal A et al (2010) Implementation of standardized international karyotype scoring practices is needed to provide uniform and systematic evaluation for patients with myelodysplastic syndrome using IPSS criteria: An International Working Group on MDS Cytogenetics Study. Leuk Res 34:160–165. doi:10.1016/j.leukres.2009.07.006

    Article  PubMed  Google Scholar 

  25. Greenberg PL, Tuechler H, Schanz J et al (2012) Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes. Blood 120:2454–2465. doi:10.1182/blood-2012-03-420489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kuendgen A, Tuechler H, Nomdedeu M et al (2015) An analysis of prognostic markers and the performance of scoring systems in 1837 patients with therapy-related myelodysplastic syndrome – a study of the International Working Group (IWG-PM) for Myelodysplastic Syndromes (MDS). Blood 126:609–609

    Google Scholar 

  27. Such E, Germing U, Malcovati L et al (2013) Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood 121:3005–3015. doi:10.1182/blood-2012-08-452938

    Article  CAS  PubMed  Google Scholar 

  28. Padron E, Garcia-Manero G, Patnaik MM et al (2015) An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. Blood Cancer J 5, e333. doi:10.1038/bcj.2015.53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nomdedeu M, Calvo X, Pereira A et al (2016) Prognostic impact of chromosomal translocations in myelodysplastic syndromes and chronic myelomonocytic leukemia patients. A study by the spanish group of myelodysplastic syndromes. Genes Chromosomes Cancer 55:322–327. doi:10.1002/gcc.22333

    Article  CAS  PubMed  Google Scholar 

  30. Breems DA, Van Putten WLJ, De Greef GE et al (2008) Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 26:4791–4797. doi:10.1200/JCO.2008.16.0259

    Article  PubMed  Google Scholar 

  31. Rücker FG, Schlenk RF, Bullinger L et al (2012) TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 119:2114–2121. doi:10.1182/blood-2011-08-375758

    Article  PubMed  Google Scholar 

  32. Grossmann V, Schnittger S, Kohlmann A et al (2012) A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood 120:2963–2972. doi:10.1182/blood-2012-03-419622

    Article  CAS  PubMed  Google Scholar 

  33. Valcárcel D, Ademà V, Solè F et al (2013) Complex, not monosomal, karyotype is the cytogenetic marker of poorest prognosis in patients with primary myelodysplastic syndrome. J Clin Oncol 31:916–922. doi:10.1200/JCO.2012.41.6073

    Article  PubMed  Google Scholar 

  34. Schanz J, Tüchler H, Solé F et al (2013) Monosomal karyotype in MDS: explaining the poor prognosis? Leukemia 27:1988–1995. doi:10.1038/leu.2013.187

    Article  CAS  PubMed  Google Scholar 

  35. Patnaik MM, Hanson CA, Hodnefield JM et al (2011) Monosomal karyotype in myelodysplastic syndromes, with or without monosomy 7 or 5, is prognostically worse than an otherwise complex karyotype. Leukemia 25:266–270. doi:10.1038/leu.2010.258

    Article  CAS  PubMed  Google Scholar 

  36. Gangat N, Patnaik MM, Begna K et al (2013) Evaluation of revised IPSS cytogenetic risk stratification and prognostic impact of monosomal karyotype in 783 patients with primary myelodysplastic syndromes. Am J Hematol 88:690–693. doi:10.1002/ajh.23477

    Article  PubMed  Google Scholar 

  37. Kolquist KA, Schultz RA, Furrow A et al (2011) Microarray-based comparative genomic hybridization of cancer targets reveals novel, recurrent genetic aberrations in the myelodysplastic syndromes. Cancer Genet 204:603–628. doi:10.1016/j.cancergen.2011.10.004

    Article  CAS  PubMed  Google Scholar 

  38. Tiu RV, Gondek LP, O'keefe CL et al (2011) Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 117:4552–4560. doi:10.1182/blood-2010-07-295857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Arenillas L, Mallo M, Ramos F et al (2013) Single nucleotide polymorphism array karyotyping: a diagnostic and prognostic tool in myelodysplastic syndromes with unsuccessful conventional cytogenetic testing. Genes Chromosomes Cancer 52:1167–1177. doi:10.1002/gcc.22112

    Article  CAS  PubMed  Google Scholar 

  40. Papaemmanuil E, Gerstung M, Malcovati L et al. (2013) Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122:3616-3627– quiz 3699. doi: 10.1182/blood-2013-08-518886

  41. Bejar R, Stevenson K, Abdel-Wahab O et al (2011) Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 364:2496–2506. doi:10.1056/NEJMoa1013343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Haferlach T, Nagata Y, Grossmann V et al (2014) Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 28:241–247. doi:10.1038/leu.2013.336

    Article  CAS  PubMed  Google Scholar 

  43. Wu L, Song L, Xu L et al (2016) Genetic landscape of recurrent ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 mutations in 304 Chinese patients with myelodysplastic syndromes. Tumour Biol 37:4633–4640. doi:10.1007/s13277-015-4305-2

    Article  CAS  PubMed  Google Scholar 

  44. Huang D, Nagata Y, Grossmann V et al (2015) BRCC3 mutations in myeloid neoplasms. Haematologica 100:1051–1057. doi:10.3324/haematol.2014.111989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jankowska AM, Szpurka H, Tiu RV et al (2009) Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 113:6403–6410. doi:10.1182/blood-2009-02-205690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Langemeijer SMC, Kuiper RP, Berends M et al (2009) Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41:838–842. doi:10.1038/ng.391

    Article  CAS  PubMed  Google Scholar 

  47. Jädersten M, Saft L, Smith A et al (2011) TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 29:1971–1979. doi:10.1200/JCO.2010.31.8576

    Article  PubMed  Google Scholar 

  48. Pellagatti A, Roy S, Di Genua C et al (2016) Targeted resequencing analysis of 31 genes commonly mutated in myeloid disorders in serial samples from myelodysplastic syndrome patients showing disease progression. Leukemia 30:247–250. doi:10.1038/leu.2015.129

    Article  CAS  PubMed  Google Scholar 

  49. Gondek LP, Tiu R, O'keefe CL et al (2008) Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood 111:1534–1542. doi:10.1182/blood-2007-05-092304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Makishima H, Jankowska AM, Tiu RV et al (2010) Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies. Leukemia 24:1799–1804. doi:10.1038/leu.2010.167

    Article  CAS  PubMed  Google Scholar 

  51. Nikoloski G, Langemeijer SMC, Kuiper RP et al (2010) Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 42:665–667. doi:10.1038/ng.620

    Article  CAS  PubMed  Google Scholar 

  52. Ernst T, Chase AJ, Score J et al (2010) Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 42:722–726. doi:10.1038/ng.621

    Article  CAS  PubMed  Google Scholar 

  53. Hou H-A, Kuo Y-Y, Tang J-L et al (2014) Clinical implications of the SETBP1 mutation in patients with primary myelodysplastic syndrome and its stability during disease progression. Am J Hematol 89:181–186. doi:10.1002/ajh.23611

    Article  CAS  PubMed  Google Scholar 

  54. Tiu RV, Visconte V, Traina F et al (2011) Updates in cytogenetics and molecular markers in MDS. Curr Hematol Malig Rep 6:126–135. doi:10.1007/s11899-011-0081-2

    Article  PubMed  Google Scholar 

  55. Fernandez-Mercado M, Pellagatti A, Di Genua C et al (2013) Mutations in SETBP1 are recurrent in myelodysplastic syndromes and often coexist with cytogenetic markers associated with disease progression. Br J Haematol 163:235–239. doi:10.1111/bjh.12491

    CAS  PubMed  Google Scholar 

  56. Dunbar AJ, Gondek LP, O'keefe CL et al (2008) 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res 68:10349–10357. doi:10.1158/0008-5472.CAN-08-2754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Makishima H, Cazzolli H, Szpurka H et al (2009) Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. J Clin Oncol 27:6109–6116. doi:10.1200/JCO.2009.23.7503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jasek M, Gondek LP, Bejanyan N et al (2010) TP53 mutations in myeloid malignancies are either homozygous or hemizygous due to copy number-neutral loss of heterozygosity or deletion of 17p. Leukemia 24:216–219. doi:10.1038/leu.2009.189

    Article  CAS  PubMed  Google Scholar 

  59. Svobodova K, Zemanova Z, Lhotska H et al (2016) Copy number neutral loss of heterozygosity at 17p and homozygous mutations of TP53 are associated with complex chromosomal aberrations in patients newly diagnosed with myelodysplastic syndromes. Leuk Res 42:7–12. doi:10.1016/j.leukres.2016.01.009

    Article  CAS  PubMed  Google Scholar 

  60. Kanagal-Shamanna R, Luthra R, Yin CC et al (2016) Myeloid neoplasms with isolated isochromosome 17q demonstrate a high frequency of mutations in SETBP1, SRSF2, ASXL1 and NRAS. Oncotarget 7:14251–14258. doi:10.18632/oncotarget.7350

    PubMed  PubMed Central  Google Scholar 

  61. Kanagal-Shamanna R, Bueso-Ramos CE, Barkoh B et al (2012) Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53. Cancer 118:2879–2888. doi:10.1002/cncr.26537

    Article  CAS  PubMed  Google Scholar 

  62. Graubert TA, Shen D, Ding L et al (2011) Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet 44:53–57. doi:10.1038/ng.1031

    Article  PubMed  PubMed Central  Google Scholar 

  63. Bacher U, Haferlach T, Schnittger S et al (2014) Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact. Br J Haematol 164:822–833. doi:10.1111/bjh.12710

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Victorian Cancer Cytogenetics Service, St. Vincent’s Hospital, 41 Victoria Parade, Fitzroy, Melbourne, VIC, 3065, Australia

    Meaghan Wall

  2. Department of Medicine, St Vincent’s Hospital, The University of Melbourne, Melbourne, Australia

    Meaghan Wall

Authors
  1. Meaghan Wall
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meaghan Wall .

Editor information

Editors and Affiliations

  1. Haematology Division Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong Prince of Wales Hospital, Shatin, Hong Kong, China

    Thomas S.K. Wan

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media LLC

About this protocol

Cite this protocol

Wall, M. (2017). Recurrent Cytogenetic Abnormalities in Myelodysplastic Syndromes. In: Wan, T. (eds) Cancer Cytogenetics. Methods in Molecular Biology, vol 1541. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6703-2_18

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-6703-2_18

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6701-8

  • Online ISBN: 978-1-4939-6703-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation