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Myelodysplasias

Accurate detection of uniparental disomy and microdeletions by SNP array analysis in myelodysplastic syndromes with normal cytogenetics

Leukemia volume 23, pages 1605–1613 (2009)Cite this article

Abstract

Progress in the management of patients with myelodysplastic syndromes (MDS) has been hampered by the inability to detect cytogenetic abnormalities in 40–60% of cases. We prospectively analyzed matched pairs of bone marrow and buccal cell (normal) DNA samples from 51 MDS patients by single nucleotide polymorphism (SNP) arrays, and identified somatically acquired clonal genomic abnormalities in 21 patients (41%). Among the 33 patients with normal bone marrow cell karyotypes, 5 (15%) had clonal, somatically acquired aberrations by SNP array analysis, including 4 with segmental uniparental disomies (UPD) and 1 with three separate microdeletions. Each abnormality was detected more readily in CD34+ cells than in unselected bone marrow cells. Paired analysis of bone marrow and buccal cell DNA from each patient was necessary to distinguish true clonal genomic abnormalities from inherited copy number variations and regions with apparent loss of heterozygosity. UPDs affecting chromosome 7q were identified in two patients who had a rapidly deteriorating clinical course despite a low-risk International Prognostic Scoring System score. Further studies of larger numbers of patients will be needed to determine whether 7q UPD detected by SNP array analysis will identify higher risk MDS patients at diagnosis, analogous to those with 7q cytogenetic abnormalities.

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References

  1. Corey SJ, Minden MD, Barber DL, Kantarjian H, Wang JC, Schimmer AD . Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer 2007; 7: 118–129.

    Article  CAS  Google Scholar 

  2. Estey E . Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol 2007; 25: 1908–1915.

    Article  Google Scholar 

  3. Nimer SD . Myelodysplastic syndromes. Blood 2008; 111: 4841–4851.

    Article  CAS  Google Scholar 

  4. de Witte T, Oosterveld M, Muus P . Autologous and allogeneic stem cell transplantation for myelodysplastic syndrome. Blood Rev 2007; 21: 49–59.

    Article  Google Scholar 

  5. Haase D, Germing U, Schanz J, Pfeilstocker M, Nosslinger T, Hildebrandt B et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 2007; 110: 4385–4395.

    Article  CAS  Google Scholar 

  6. List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352: 549–557.

    Article  CAS  Google Scholar 

  7. Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 2008; 451: 335–339.

    Article  CAS  Google Scholar 

  8. Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007; 109: 52–57.

    Article  CAS  Google Scholar 

  9. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002; 20: 2429–2440.

    Article  CAS  Google Scholar 

  10. Heinrichs S, Look AT . Identification of structural aberrations in cancer by SNP array analysis. Genome Biol 2007; 8: 219.

    Article  Google Scholar 

  11. Gondek LP, Dunbar AJ, Szpurka H, McDevitt MA, Maciejewski JP . SNP array karyotyping allows for the detection of uniparental disomy and cryptic chromosomal abnormalities in MDS/MPD-U and MPD. PLoS ONE 2007; 2: e1225.

    Article  Google Scholar 

  12. Gondek LP, Haddad AS, O'Keefe CL, Tiu R, Wlodarski MW, Sekeres MA et al. Detection of cryptic chromosomal lesions including acquired segmental uniparental disomy in advanced and low-risk myelodysplastic syndromes. Exp Hematol 2007; 35: 1728–1738.

    Article  CAS  Google Scholar 

  13. Gondek LP, Tiu R, Haddad AS, O'Keefe CL, Sekeres MA, Theil KS et al. Single nucleotide polymorphism arrays complement metaphase cytogenetics in detection of new chromosomal lesions in MDS. Leukemia 2007; 21: 2058–2061.

    Article  CAS  Google Scholar 

  14. Gondek LP, Tiu R, O'Keefe CL, Sekeres MA, Theil KS, Maciejewski JP . Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood 2008; 111: 1534–1542.

    Article  CAS  Google Scholar 

  15. Mohamedali A, Gaken J, Twine NA, Ingram W, Westwood N, Lea NC et al. Prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in low-risk myelodysplastic syndromes. Blood 2007; 110: 3365–3373.

    Article  CAS  Google Scholar 

  16. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189–199.

    Article  CAS  Google Scholar 

  17. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

    CAS  Google Scholar 

  18. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835–3849.

    Article  CAS  Google Scholar 

  19. Lin M, Wei LJ, Sellers WR, Lieberfarb M, Wong WH, Li C . dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 2004; 20: 1233–1240.

    Article  CAS  Google Scholar 

  20. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 2007; 449: 851–861.

    Article  CAS  Google Scholar 

  21. Liu TX, Becker MW, Jelinek J, Wu WS, Deng M, Mikhalkevich N et al. Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Nat Med 2007; 13: 78–83.

    Article  Google Scholar 

  22. Boultwood J, Fidler C, Strickson AJ, Watkins F, Gama S, Kearney L et al. Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome. Blood 2002; 99: 4638–4641.

    Article  CAS  Google Scholar 

  23. Le Beau MM, Espinosa III R, Neuman WL, Stock W, Roulston D, Larson RA et al. Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases. Proc Natl Acad Sci USA 1993; 90: 5484–5488.

    Article  CAS  Google Scholar 

  24. Poppe B, Vandesompele J, Schoch C, Lindvall C, Mrozek K, Bloomfield CD et al. Expression analyses identify MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies. Blood 2004; 103: 229–235.

    Article  CAS  Google Scholar 

  25. Zatkova A, Schoch C, Speleman F, Poppe B, Mannhalter C, Fonatsch C et al. GAB2 is a novel target of 11q amplification in AML/MDS. Genes Chromosomes Cancer 2006; 45: 798–807.

    Article  CAS  Google Scholar 

  26. McEachern MJ, Haber JE . Break-induced replication and recombinational telomere elongation in yeast. Annu Rev Biochem 2006; 75: 111–135.

    Article  CAS  Google Scholar 

  27. Harada H, Harada Y, Niimi H, Kyo T, Kimura A, Inaba T . High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 2004; 103: 2316–2324.

    Article  CAS  Google Scholar 

  28. Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Takeuchi K, Maki K et al. Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis. Blood 2000; 96: 3154–3160.

    CAS  PubMed  Google Scholar 

  29. Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK . A high-resolution survey of deletion polymorphism in the human genome. Nat Genet 2006; 38: 75–81.

    Article  CAS  Google Scholar 

  30. Khaja R, Zhang J, MacDonald JR, He Y, Joseph-George AM, Wei J et al. Genome assembly comparison identifies structural variants in the human genome. Nat Genet 2006; 38: 1413–1418.

    Article  CAS  Google Scholar 

  31. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD et al. Global variation in copy number in the human genome. Nature 2006; 444: 444–454.

    Article  CAS  Google Scholar 

  32. Zhang J, Feuk L, Duggan GE, Khaja R, Scherer SW . Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome. Cytogenet Genome Res 2006; 115: 205–214.

    Article  CAS  Google Scholar 

  33. Knudson Jr AG . Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68: 820–823.

    Article  Google Scholar 

  34. Fitzgibbon J, Smith LL, Raghavan M, Smith ML, Debernardi S, Skoulakis S et al. Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias. Cancer Res 2005; 65: 9152–9154.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Martin H Nguyen and Michael Fernandez (MDACC) as well as Nikki Flores and Elena Wang (USCF) for excellent technical assistance and we are grateful to John Gilbert for editorial review and helpful discussions. We also thank Lorna Mangus for administrative support. The work was supported in part by NIH P01 Grant CA-108631 from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    S Heinrichs, R V Kulkarni & A T Look

  2. Department of Hematopathology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    C E Bueso-Ramos

  3. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    R L Levine

  4. Department of Pediatrics, University of California, San Francisco, CA, USA

    M L Loh

  5. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    C Li & D Neuberg

  6. Department of Stem Cell Transplantation Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    S M Kornblau

  7. Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    J-P Issa, G Garcia-Manero & H M Kantarjian

  8. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA

    D G Gilliland

  9. Division of Hematology, University of Washington Medical Center and Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    E H Estey

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  1. S Heinrichs
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Correspondence to A T Look.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Heinrichs, S., Kulkarni, R., Bueso-Ramos, C. et al. Accurate detection of uniparental disomy and microdeletions by SNP array analysis in myelodysplastic syndromes with normal cytogenetics. Leukemia 23, 1605–1613 (2009). https://doi.org/10.1038/leu.2009.82

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