Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Acute lymphoblastic leukemia

Array-based comparative genomic hybridization detects copy number variations with prognostic relevance in 80% of ALL with normal karyotype or failed chromosome analysis

Abstract

Pretreatment cytogenetics is an important parameter for risk stratification and therapy approach in acute lymphoblastic leukemia (ALL). However, in up to 30% of cases, chromosome banding analysis (CBA) fails or reveals a normal karyotype. To characterize the subset of ALL with normal karyotype or failed CBA, we performed fluorescence in situ hybridization (FISH) or PCR for BCR-ABL1 and MLL rearrangements as well as array comparative genomic hybridization (aCGH) in 186 adult patients. We further carried out FISH for MYC in cases with Burkitt leukemia phenotype. FISH or PCR revealed one of the respective rearrangements in 22% of patients. In 80% of cases, copy number variations (CNV) were identified by aCGH. In 22% of cases, all CNV were below the resolution of CBA. On the basis of results of FISH, RT-PCR and aCGH, patients were categorized into three groups. The novel subset of patients with submicroscopic CNV only showed an overall survival at 3 years of 84% compared with 64% for patients classified as adverse abnormalities and 77% for cases with other aberrations (P=0.046). Thus, ALL with non-informative CBA can be further classified by FISH and aCGH providing prognostic information, which may be useful for a more individualized therapy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th ed. International Agency for Research on Cancer (IARC): Lyon, France, 2008.

    Google Scholar 

  2. Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 2007; 109: 3189–3197.

    Article  CAS  Google Scholar 

  3. Harrison CJ, Foroni L . Cytogenetics and molecular genetics of acute lymphoblastic leukemia. Rev Clin Exp Hematol 2002; 6: 91–113.

    Article  CAS  Google Scholar 

  4. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976; 33: 451–458.

    Article  CAS  Google Scholar 

  5. Pui CH, Relling MV, Downing JR . Acute lymphoblastic leukemia. N Engl J Med 2004; 350: 1535–1548.

    Article  CAS  Google Scholar 

  6. Iacobucci I, Papayannidis C, Lonetti A, Ferrari A, Baccarani M, Martinelli G . Cytogenetic and molecular predictors of outcome in acute lymphocytic leukemia: recent developments. Curr Hematol Malig Rep 2012; 7: 133–143.

    Article  Google Scholar 

  7. Graux C, Cools J, Michaux L, Vandenberghe P, Hagemeijer A . Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia 2006; 20: 1496–1510.

    Article  CAS  Google Scholar 

  8. Ottmann OG, Wassmann B . Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2005; 1: 118–122.

    Article  Google Scholar 

  9. Hastings R, Howell R, Betts D, Porter S, Haferlach C, Dastugue N et al. Guidelines and Quality Assurance for Acquired Cytogenetics. A common European framework for quality assessment for banded chromosome studies and molecular cytogenetic investigation of acquired abnormalities. European Cytogeneticists Association Newsletter 2013; No. 31.

  10. Haferlach C, Rieder H, Lillington DM, Dastugue N, Hagemeijer A, Harbott J et al. Proposals for standardized protocols for cytogenetic analyses of acute leukemias, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, and myelodysplastic syndromes. Genes Chromosomes Cancer 2007; 46: 494–499.

    Article  CAS  Google Scholar 

  11. Huh J, Jung CW, Kim HJ, Kim YK, Moon JH, Sohn SK et al. Different characteristics identified by single nucleotide polymorphism array analysis in leukemia suggest the need for different application strategies depending on disease category. Genes Chromosomes Cancer 2013; 52: 44–55.

    Article  CAS  Google Scholar 

  12. Löffler H, Rastetter J, Haferlach T . Atlas of Clinical Hematology 6th ed. Springer: Heidelberg, Germany, 2010.

    Google Scholar 

  13. Mühlbacher V, Zenger M, Schnittger S, Weissmann S, Kunze F, Kohlmann A et al. Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%. Genes Chromosomes Cancer 2014; 53: 524–536.

    Article  Google Scholar 

  14. Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995; 9: 1783–1786.

    CAS  Google Scholar 

  15. Schoch C, Haferlach T . Cytogenetics in acute myeloid leukemia. Curr Oncol Rep 2002; 4: 390–397.

    Article  Google Scholar 

  16. Shaffer LG, McGowan-Jordan J, Schmid M . ISCN 2013: An International System for Human Cytogenetic Nomenclature. Karger; Basel: New York, 2013.

    Google Scholar 

  17. Cross NC, Melo JV, Feng L, Goldman JM . An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders. Leukemia 1994; 8: 186–189.

    CAS  PubMed  Google Scholar 

  18. Repp R, Borkhardt A, Haupt E, Keuder J, Brettreich S, Hammermann J et al. Detection of four different 11q23 chromosomal abnormalities by multiplex-PCR and fluorescence-based automatic DNA-fragment analysis. Leukemia 1995; 9: 210–215.

    CAS  PubMed  Google Scholar 

  19. MacDonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW . The database of genomic variants: a curated collection of structural variation in the human genome. Nucleic Acids Res 2013; 42: D986–D992.

    Article  Google Scholar 

  20. Pui CH, Carroll AJ, Raimondi SC, Land VJ, Crist WM, Shuster JJ et al. Clinical presentation, karyotypic characterization, and treatment outcome of childhood acute lymphoblastic leukemia with a near-haploid or hypodiploid less than 45 line. Blood 1990; 75: 1170–1177.

    CAS  PubMed  Google Scholar 

  21. Charrin C, Thomas X, Ffrench M, Le QH, Andrieux J, Mozziconacci MJ et al. A report from the LALA-94 and LALA-SA groups on hypodiploidy with 30 to 39 chromosomes and near-triploidy: 2 possible expressions of a sole entity conferring poor prognosis in adult acute lymphoblastic leukemia (ALL). Blood 2004; 104: 2444–2451.

    Article  CAS  Google Scholar 

  22. Safavi S, Forestier E, Golovleva I, Barbany G, Nord KH, Moorman AV et al. Loss of chromosomes is the primary event in near-haploid and low-hypodiploid acute lymphoblastic leukemia. Leukemia 2013; 27: 248–250.

    Article  CAS  Google Scholar 

  23. Kowalczyk JR, Babicz M, Gaworczyk A, Lejman M, Winnicka D, Styka B et al. Structural and numerical abnormalities resolved in one-step analysis: the most common chromosomal rearrangements detected by comparative genomic hybridization in childhood acute lymphoblastic leukemia. Cancer Genet Cytogenet 2010; 200: 161–166.

    Article  CAS  Google Scholar 

  24. Matteucci C, Barba G, Varasano E, Vitale A, Mancini M, Testoni N et al. Rescue of genomic information in adult acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics: a GIMEMA centralized biological study. Br J Haematol 2010; 149: 70–78.

    Article  Google Scholar 

  25. Kuchinskaya E, Heyman M, Nordgren A, Schoumans J, Staaf J, Borg A et al. Array-CGH reveals hidden gene dose changes in children with acute lymphoblastic leukaemia and a normal or failed karyotype by G-banding. Br J Haematol 2008; 140: 572–577.

    Article  Google Scholar 

  26. Simons A, Stevens-Kroef M, Idrissi-Zaynoun NE, van Gessel S, Weghuis DO, van den Berg E et al. Microarray-based genomic profiling as a diagnostic tool in acute lymphoblastic leukemia. Genes Chromosomes Cancer 2011; 50: 969–981.

    Article  CAS  Google Scholar 

  27. Usvasalo A, Raty R, Harila-Saari A, Koistinen P, Savolainen ER, Vettenranta K et al. Acute lymphoblastic leukemias with normal karyotypes are not without genomic aberrations. Cancer Genet Cytogenet 2009; 192: 10–17.

    Article  CAS  Google Scholar 

  28. Van Rhee F, Kasprzyk A, Jamil A, Dickinson H, Lin F, Cross NC et al. l. Detection of the BCR-ABL gene by reverse transcription/polymerase chain reaction and fluorescence in situ hybridization in a patient with Philadelphia chromosome negative acute lymphoblastic leukaemia. Br J Haematol 1995; 90: 225–228.

    Article  CAS  Google Scholar 

  29. Kowarz E, Burmeister T, Lo NL, Jansen MW, Delabesse E, Klingebiel T et al. Complex MLL rearrangements in t(4;11) leukemia patients with absent AF4.MLL fusion allele. Leukemia 2007; 21: 1232–1238.

    Article  CAS  Google Scholar 

  30. De Braekeleer E, Meyer C, Douet-Guilbert N, Basinko A, Le Bris MJ, Morel F et al. Identification of MLL partner genes in 27 patients with acute leukemia from a single cytogenetic laboratory 15. Mol Oncol 2011; 5: 555–563.

    Article  CAS  Google Scholar 

  31. Pelz AF, Kroning H, Franke A, Wieacker P, Stumm M . High reliability and sensitivity of the BCR/ABL1 D-FISH test for the detection of BCR/ABL rearrangements. Ann Hematol 2002; 81: 147–153.

    Article  CAS  Google Scholar 

  32. Suela J, Alvarez S, Cifuentes F, Largo C, Ferreira BI, Blesa D et al. DNA profiling analysis of 100 consecutive de novo acute myeloid leukemia cases reveals patterns of genomic instability that affect all cytogenetic risk groups. Leukemia 2007; 21: 1224–1231.

    Article  CAS  Google Scholar 

  33. Haferlach C, Zenger M, Staller M, Roller A, Raitner K, Holzwarth J et al. Array CGH identifies copy number changes in 10% of 520 MDS patients with normal karyotype: deletions encompass the genes TET2, DNMT3A, ETV6, NF1, RUNX1, and STAG2 and are associated with shorter survival. Blood 2013; 122: 633a.

    Article  Google Scholar 

  34. Paulsson K, Cazier JB, Macdougall F, Stevens J, Stasevich I, Vrcelj N et al. Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: Unexpected similarities with pediatric disease. Proc Natl Acad Sci USA 2008; 105: 6708–6713.

    Article  CAS  Google Scholar 

  35. Yasar D, Karadogan I, Alanoglu G, Akkaya B, Luleci G, Salim O et al. Array comparative genomic hybridization analysis of adult acute leukemia patients. Cancer Genet Cytogenet 2010; 197: 122–129.

    Article  CAS  Google Scholar 

  36. Okamoto R, Ogawa S, Nowak D, Kawamata N, Akagi T, Kato M et al. Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric acute lymphoblastic leukemia. Haematologica 2010; 95: 1481–1488.

    Article  CAS  Google Scholar 

  37. Safavi S, Hansson M, Karlsson K, Biloglav A, Johansson B, Paulsson K . Novel gene targets detected by genomic profiling in a consecutive series of 126 adults with acute lymphoblastic leukemia. Haematologica 2015; 100: 55–61.

    Article  CAS  Google Scholar 

  38. Harrison CJ, Moorman AV, Broadfield ZJ, Cheung KL, Harris RL, Reza JG et al. Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia. Br J Haematol 2004; 125: 552–559.

    Article  Google Scholar 

  39. Mandahl N, Johansson B, Mertens F, Mitelman F . Disease-associated patterns of disomic chromosomes in hyperhaploid neoplasms. Genes Chromosomes Cancer 2012; 51: 536–544.

    Article  CAS  Google Scholar 

  40. Gokbuget N, Hoelzer D . Treatment of adult acute lymphoblastic leukemia. Semin Hematol 2009; 46: 64–75.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C Haferlach.

Ethics declarations

Competing interests

CH, TH, WK and SS declare part ownership of MLL Munich Leukemia Laboratory. VM and MZ are employed by MLL Munich Leukemia Laboratory.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mühlbacher, V., Haferlach, T., Kern, W. et al. Array-based comparative genomic hybridization detects copy number variations with prognostic relevance in 80% of ALL with normal karyotype or failed chromosome analysis. Leukemia 30, 318–324 (2016). https://doi.org/10.1038/leu.2015.276

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.276

This article is cited by

Search

Quick links