The Use of Cytogenetic Microarrays in Myelodysplastic Syndrome Characterization

  • Lisa G. Shaffer
  • Blake C. Ballif
  • Roger A. Schultz
Part of the Methods in Molecular Biology book series (MIMB, volume 973)


Various microarray platforms, including BAC, oligonucleotide, and SNP arrays, have been shown to ­provide clinically useful diagnostic and prognostic information for patients with myelodysplastic syndromes (MDS). Clinically useful arrays are designed with specific purposes in mind and with attention to genomic content and probe density. All array types have been shown to detect genomic copy gains and losses, with SNP arrays having the added advantage of detecting copy neutral loss of heterozygosity (CNLOH). The finding of CNLOH has led to the identification of certain disease genes implicated in the initiation or progression of myeloid diseases. In addition, SNP karyotyping alone, or in conjunction with routine cytogenetics, can affect the outcome prediction and improve prognostic stratification of patients with MDS. Patients who were reclassified after array testing as having adverse-risk chromosomal findings correlated with poor survival. Results of over 25 published studies support the use of arrays in MDS testing. Because few balanced translocations are found in MDS, this disease is particularly amenable to microarray testing, and studies have shown better disease classification, identification of cryptic changes, and prognostication in this heterogeneous group of disorders. Novel genomic alterations identified by array testing may lead to better targeted therapies for treating patients with MDS.

Key words

Myelodysplastic syndrome MDS Microarray aCGH SNP Copy number variant CNV Cytogenetics Cancer 



The authors thank Erin Dodge (Signature Genomic Laboratories) for her careful formatting of this manuscript. We thank Donna Wilmoth, (The Children’s Hospital of Philadelphia) for the use of the SNP image.


  1. 1.
    Ma X, Does M, Raza A et al (2007) Myelodysplastic syndromes: incidence and survival in the United States. Cancer 109(8):1536–1542. doi:10.1002/cncr.22570 PubMedCrossRefGoogle Scholar
  2. 2.
    Greenberg P, Cox C, Lebeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89(6):2079–2088PubMedGoogle Scholar
  3. 3.
    Bernasconi P, Cavigliano PM, Boni M et al (2003) Is fish a relevant prognostic tool in myelodysplastic syndromes with a normal chromosome pattern on conventional cytogenetics? A study on 57 patients. Leukemia 17(11):2107–2112. doi:10.1038/sj.leu.2403108 2403108 [pii] PubMedCrossRefGoogle Scholar
  4. 4.
    Rigolin GM, Bigoni R, Milani R et al (2001) Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype. Leukemia 15(12):1841–1847PubMedCrossRefGoogle Scholar
  5. 5.
    List A, Dewald G, Bennett J et al (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355(14):1456–1465. doi:355/14/1456 [pii] 10.1056/NEJMoa061292 PubMedCrossRefGoogle Scholar
  6. 6.
    Giagounidis AA, Germing U, Strupp C et al (2005) Prognosis of patients with del(5q) mds and complex karyotype and the possible role of lenalidomide in this patient subgroup. Ann Hematol 84(9):569–571. doi:10.1007/s00277-005-1054-0 PubMedCrossRefGoogle Scholar
  7. 7.
    Lubbert M, Wijermans P, Kunzmann R et al (2001) Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Br J Haematol 114(2):349–357. doi:bjh2933 [pii] PubMedCrossRefGoogle Scholar
  8. 8.
    Raj K, John A, Ho A et al (2007) Cdkn2b methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. Leukemia 21(9):1937–1944. doi:2404796 [pii] 10.1038/sj.leu.2404796 PubMedCrossRefGoogle Scholar
  9. 9.
    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(3):1534–1542. doi:blood-2007-05-092304 [pii] 10.1182/blood-2007-05-092304 PubMedCrossRefGoogle Scholar
  10. 10.
    Mohamedali A, Gaken J, Twine NA et al (2007) Prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in low-risk myelodysplastic syndromes. Blood 110(9):3365–3373. doi:blood-2007-03-079673 [pii] 10.1182/blood-2007-03-079673 PubMedCrossRefGoogle Scholar
  11. 11.
    Paulsson K, Heidenblad M, Strombeck B et al (2006) High-resolution genome-wide array-based comparative genome hybridization reveals cryptic chromosome changes in aml and mds cases with trisomy 8 as the sole cytogenetic aberration. Leukemia 20(5):840–846. doi:2404145 [pii] 10.1038/sj.leu.2404145 PubMedCrossRefGoogle Scholar
  12. 12.
    Evers C, Beier M, Poelitz A et al (2007) Molecular definition of chromosome arm 5q deletion end points and detection of hidden aberrations in patients with myelodysplastic syndromes and isolated del(5q) using oligonucleotide array cgh. Genes Chromosomes Cancer 46(12):1119–1128. doi:10.1002/gcc.20498 PubMedCrossRefGoogle Scholar
  13. 13.
    Starczynowski DT, Vercauteren S, Telenius A et al (2008) High-resolution whole genome tiling path array cgh analysis of cd34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival. Blood 112(8):3412–3424. doi:blood-2007-11-122028 [pii] 10.1182/blood-2007-11-122028 PubMedCrossRefGoogle Scholar
  14. 14.
    Kallioniemi A, Kallioniemi OP, Sudar D et al (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258(5083):818–821PubMedCrossRefGoogle Scholar
  15. 15.
    Derisi J, Penland L, Brown PO et al (1996) Use of a cdna microarray to analyse gene expression patterns in human cancer. Nat Genet 14(4):457–460PubMedCrossRefGoogle Scholar
  16. 16.
    Lucito R, Healy J, Alexander J et al (2003) Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation. Genome Res 13(10):2291–2305PubMedCrossRefGoogle Scholar
  17. 17.
    Pinkel D, Segraves R, Sudar D et al (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20(2):207–211PubMedCrossRefGoogle Scholar
  18. 18.
    Schena M, Shalon D, Davis RW et al (1995) Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270(5235):467–470PubMedCrossRefGoogle Scholar
  19. 19.
    Solinas-Toldo S, Lampel S, Stilgenbauer S et al (1997) Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20(4):399–407PubMedCrossRefGoogle Scholar
  20. 20.
    Kralovics R, Teo SS, Buser AS et al (2005) Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the v617f mutation of jak2. Blood 106(10):3374–3376. doi:2005-05-1889 [pii] 10.1182/blood-2005-05-1889 PubMedCrossRefGoogle Scholar
  21. 21.
    O’keefe CL, Tiu R, Gondek LP et al (2007) High-resolution genomic arrays facilitate detection of novel cryptic chromosomal lesions in myelodysplastic syndromes. Exp Hematol 35(2):240–251. doi:S0301-472X(06)00637-0 [pii] 10.1016/j.exphem.2006.09.016 PubMedCrossRefGoogle Scholar
  22. 22.
    Akagi T, Ogawa S, Dugas M et al (2009) Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype. Haematologica 94(2):213–223. doi:haematol.13024 [pii] 10.3324/haematol.13024 PubMedCrossRefGoogle Scholar
  23. 23.
    Kim JE, Woo KS, Kim KE et al (2010) Duplications of the long arm of both chromosome 1, dup(1)(q21q32), leading to tetrasomy 1q in myelodysplastic syndrome. Leuk Res 34(8):e210–212. doi:S0145-2126(10)00111-6 [pii] 10.1016/j.leukres.2010.02.028 PubMedCrossRefGoogle Scholar
  24. 24.
    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(17):4552–4560. doi:blood-2010-07-295857 [pii] 10.1182/blood-2010-07-295857 PubMedCrossRefGoogle Scholar
  25. 25.
    Koken MH, Daniel MT, Gianni M et al (1999) Retinoic acid, but not arsenic trioxide, degrades the plzf/raralpha fusion protein, without inducing terminal differentiation or apoptosis, in a ra-therapy resistant t(11;17)(q23;q21) apl patient. Oncogene 18(4):1113–1118. doi:10.1038/sj.onc.1202414 PubMedCrossRefGoogle Scholar
  26. 26.
    Iafrate AJ, Feuk L, Rivera MN et al (2004) Detection of large-scale variation in the human genome. Nat Genet 36(9):949–951PubMedCrossRefGoogle Scholar
  27. 27.
    Sebat J, Lakshmi B, Troge J et al (2004) ­Large-scale copy number polymorphism in the human genome. Science 305(5683):525–528PubMedCrossRefGoogle Scholar
  28. 28.
    Sharp AJ (2009) Emerging themes and new challenges in defining the role of structural variation in human disease. Hum Mutat 30(2):135–144. doi:10.1002/humu.20843 PubMedCrossRefGoogle Scholar
  29. 29.
    Cooper GM, Coe BP, Girirajan S et al (2011) A copy number variation morbidity map of developmental delay. Nat Genet. doi:10.1038/ng.909 Google Scholar
  30. 30.
    (2007) Database of genomic variants—a curated catalogue of structural variation in the human genome. The Centre for Applied Genomics. Accessed 31 Aug 2011Google Scholar
  31. 31.
    International hapmap project (2011) International HapMap Project. Accessed 31 Aug 2011Google Scholar
  32. 32.
    Wellcome trust case control consortium (2009) Wellcome Trust. Accessed 31 Aug 2011Google Scholar
  33. 33.
    Hgdp-ceph human genome diversity cell line panel (2011) Human Polymorphism Study Center. Accessed 31 Aug 2011Google Scholar
  34. 34.
    Wholley D, Manolio T, Brooks L et al (2011) Genetic association information network (gain). National human Genome Research Institute. Accessed 31 Aug 2011Google Scholar
  35. 35.
    Illumina icontroldb. (2011) Illumina, Inc. Accessed 31 Aug 2011Google Scholar
  36. 36.
    Heinrichs S, Li C, Look AT (2010) Snp array analysis in hematologic malignancies: avoiding false discoveries. Blood 115(21):4157–4161. doi:blood-2009-11-203182 [pii] 10.1182/blood-2009-11-203182PubMedCrossRefGoogle Scholar
  37. 37.
    Praulich I, Tauscher M, Gohring G et al (2010) Clonal heterogeneity in childhood myelodysplastic syndromes-challenge for the detection of chromosomal imbalances by array-cgh. Genes Chromosomes Cancer 49(10):885–900. doi:10.1002/gcc.20797 PubMedCrossRefGoogle Scholar
  38. 38.
    Slovak ML, Smith DD, Bedell V et al (2010) Assessing karyotype precision by microarray-based comparative genomic hybridization in the myelodysplastic/myeloproliferative syndromes. Mol Cytogenet 3:23. doi:1755-8166-3-23 [pii] 10.1186/1755-8166-3-23 PubMedCrossRefGoogle Scholar
  39. 39.
    Borze I, Juvonen E, Ninomiya S et al (2010) High-resolution oligonucleotide array comparative genomic hybridization study and methylation status of the rps14 gene in de novo myelodysplastic syndromes. Cancer Genet Cytogenet 197(2):166–173. doi:S0165-4608(09)­00664-5 [pii] 10.1016/j.cancergen­cyto.2009.11.012 PubMedCrossRefGoogle Scholar
  40. 40.
    Thiel A, Beier M, Ingenhag D et al (2011) Comprehensive array cgh of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance. Leukemia 25(3):387–399. doi:leu2010293 [pii] 10.1038/leu.2010.293 PubMedCrossRefGoogle Scholar
  41. 41.
    Bajaj R, Xu F, Xiang B et al (2011) Evidence-based genomic diagnosis characterized chromosomal and cryptic imbalances in 30 elderly patients with myelodysplastic syndrome and acute myeloid leukemia. Mol Cytogenet 4:3. doi:1755-8166-4-3 [pii] 10.1186/1755-8166-4-3 PubMedCrossRefGoogle Scholar
  42. 42.
    Huh J, Tiu RV, Gondek LP et al (2010) Characterization of chromosome arm 20q abnormalities in myeloid malignancies using genome-wide single nucleotide polymorphism array analysis. Genes Chromosomes Cancer 49(4):390–399. doi:10.1002/gcc.20748 PubMedGoogle Scholar
  43. 43.
    Afable MG 2nd, Wlodarski M, Makishima H et al (2011) Snp array-based karyotyping: differences and similarities between aplastic anemia and hypocellular myelodysplastic syndromes. Blood 117(25):6876–6884. doi:blood-2010-11-314393 [pii] 10.1182/blood-2010-11-314393 PubMedCrossRefGoogle Scholar
  44. 44.
    Gibson J, Morton NE, Collins A (2006) Extended tracts of homozygosity in outbred human populations. Hum Mol Genet 15(5):789–795. doi:ddi493 [pii] 10.1093/hmg/ddi493 PubMedCrossRefGoogle Scholar
  45. 45.
    Quentin S, Cuccuini W, Ceccaldi R et al (2011) Myelodysplasia and leukemia of fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic runx1/aml1 lesions. Blood 117(15):e161–170. doi:blood-2010-09-308726 [pii] 10.1182/blood-2010-09-308726 PubMedCrossRefGoogle Scholar
  46. 46.
    Wang L, Fidler C, Nadig N et al (2008) Genome-wide analysis of copy number changes and loss of heterozygosity in myelodysplastic syndrome with del(5q) using high-density single nucleotide polymorphism arrays. Haematologica 93(7):994–1000. doi:haematol.12603 [pii] 10.3324/haematol.12603 PubMedCrossRefGoogle Scholar
  47. 47.
    Heinrichs S, Kulkarni RV, Bueso-Ramos CE et al (2009) Accurate detection of uniparental disomy and microdeletions by snp array analysis in myelodysplastic syndromes with normal cytogenetics. Leukemia 23(9):1605–1613. doi:leu200982 [pii] 10.1038/leu.2009.82 PubMedCrossRefGoogle Scholar
  48. 48.
    Jankowska AM, Szpurka H, Tiu RV et al (2009) Loss of heterozygosity 4q24 and tet2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 113(25):6403–6410. doi:blood-2009-02-205690 [pii] 10.1182/blood-2009-02-205690 PubMedCrossRefGoogle Scholar
  49. 49.
    Flach J, Dicker F, Schnittger S et al (2011) An accumulation of cytogenetic and molecular genetic events characterizes the progression from mds to secondary aml: an analysis of 38 paired samples analyzed by cytogenetics, molecular mutation analysis and snp microarray profiling. Leukemia 25(4):713–718. doi:leu2010304 [pii] 10.1038/leu.2010.304 PubMedCrossRefGoogle Scholar
  50. 50.
    Makishima H, Rataul M, Gondek LP et al (2010) Fish and snp-a karyotyping in myelodysplastic syndromes: improving cytogenetic detection of del(5q), monosomy 7, del(7q), trisomy 8 and del(20q). Leuk Res 34(4):447–453. doi:S0145-2126(09)00428-7 [pii] 10.1016/j.leukres.2009.08.023 PubMedCrossRefGoogle Scholar
  51. 51.
    Greisman HA, Yi HS, Hoffman NG (2007) Transcgh: rapid identification and high-resolution mapping of balanced igh translocations in archival DNA using custom oligonucleotide arrays. Paper presented at the American Society of Hematology Annual Meeting, Atlanta, GAGoogle Scholar
  52. 52.
    Greisman HA, Greiner TC, Yi HS et al (2008) High-throughput cloning of t(11;14) breakpoints outside the major translocation cluster in mantle cell lymphoma. Paper presented at the American Society of Hematology Annual Meeting, San Francisco, CAGoogle Scholar
  53. 53.
    Valli R, Marletta C, Pressato B et al (2011) Comparative genomic hybridization on microarray (a-cgh) in constitutional and acquired mosaicism may detect as low as 8% abnormal cells. Mol Cytogenet 4:13. doi:1755-8166-4-13 [pii] 10.1186/1755-8166-4-13 PubMedCrossRefGoogle Scholar
  54. 54.
    Cross J, Peters G, Wu Z et al (2007) Resolution of trisomic mosaicism in prenatal diagnosis: estimated performance of a 50k snp microarray. Prenat Diagn 27(13):1197–1204. doi:10.1002/pd.1884 PubMedCrossRefGoogle Scholar
  55. 55.
    Neill NJ, Torchia BS, Bejjani BA et al (2010) Comparative analysis of copy number detection by whole-genome bac and oligonucleotide array cgh. Mol Cytogenet 3:11. doi:1755-8166-3-11 [pii] 10.1186/1755-8166-3-11 PubMedCrossRefGoogle Scholar
  56. 56.
    Sweetser DA, Peniket AJ, Haaland C et al (2005) Delineation of the minimal commonly deleted segment and identification of candidate tumor-suppressor genes in del(9q) acute myeloid leukemia. Genes Chromosomes Cancer 44(3):279–291. doi:10.1002/gcc.20236 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Lisa G. Shaffer
    • 1
  • Blake C. Ballif
    • 1
  • Roger A. Schultz
    • 1
  1. 1.Signature Genomic LaboratoriesPerkinElmer Inc.SpokaneUSA

Personalised recommendations