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:

Cytogenetics and Molecular Genetics

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 volume 20, pages 840–846 (2006)Cite this article

Abstract

Although trisomy 8 as the sole chromosome aberration is the most common numerical abnormality in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), little is known about its pathogenetic effects. Considering that +8 is a frequent secondary change in AML/MDS, cryptic – possibly primary – genetic aberrations may occur in cases with trisomy 8 as the apparently single anomaly. However, no such hidden anomalies have been reported. We performed a high-resolution genome-wide array-based comparative genome hybridization (array CGH) analysis of 10 AML/MDS cases with isolated +8, utilizing a 32K bacterial artificial chromosome array set, providing >98% coverage of the genome with a resolution of 100 kb. Array CGH revealed intrachromosomal imbalances, not corresponding to known genomic copy number polymorphisms, in 4/10 cases, comprising nine duplications and hemizygous deletions ranging in size from 0.5 to 2.2 Mb. A 1.8 Mb deletion at 7p14.1, which had occurred prior to the +8, was identified in MDS transforming to AML. Furthermore, a deletion including ETV6 was present in one case. The remaining seven imbalances involved more than 40 genes. The present results show that cryptic genetic abnormalities are frequent in trisomy 8-positive AML/MDS cases and that +8 as the sole cytogenetic aberration is not always the primary genetic event.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

Similar content being viewed by others

References

  1. Mitelman F, Johansson B, Mertens F . Mitelman database of chromosome aberrations in cancer. 2005. http://cgap.nci.nih.gov/Chromosomes/Mitelman.

  2. Paulsson K, Säll T, Fioretos T, Mitelman F, Johansson B . The incidence of trisomy 8 as a sole chromosomal aberration in myeloid malignancies varies in relation to gender, age, prior iatrogenic genotoxic exposure, and morphology. Cancer Genet Cytogenet 2001; 130: 160–165.

    Article  CAS  Google Scholar 

  3. Albin M, Björk J, Welinder H, Tinnerberg H, Mauritzson N, Johansson B et al. Acute myeloid leukemia and clonal chromosome aberrations in relation to past exposure to organic solvents. Scand J Work Environ Health 2000; 26: 482–491.

    Article  CAS  Google Scholar 

  4. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. Blood 1998; 92: 2322–2333.

    CAS  Google Scholar 

  5. Wolman SR, Gundacker H, Appelbaum FR, Slovak ML . Impact of trisomy 8 (+8) on clinical presentation, treatment response, and survival in acute myeloid leukemia: a southwest oncology group study. Blood 2002; 100: 29–35.

    Article  CAS  Google Scholar 

  6. Solé F, Espinet B, Sanz GF, Cervera J, Calasanz MJ, Luño E et al. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Br J Haematol 2000; 108: 346–356.

    Article  Google Scholar 

  7. Maserati E, Aprili F, Vinante F, Locatelli F, Amendola G, Zatterale A et al. Trisomy 8 in myelodysplasia and acute leukemia is constitutional in 15–20% of cases. Genes Chromosomes Cancer 2002; 33: 93–97.

    Article  CAS  Google Scholar 

  8. Nilsson L, Åstrand-Grundström I, Anderson K, Arvidsson I, Hokland P, Bryder D et al. Involvement and functional impairment of the CD34+CD38-Thy-1+ hematopoietic stem cell pool in myelodysplatic syndromes with trisomy 8. Blood 2002; 100: 259–267.

    CAS  Google Scholar 

  9. Schoch C, Kohlmann A, Dugas M, Kern W, Hiddemann W, Schnittger S et al. Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q. Leukemia 2005; 19: 1224–1228.

    Article  CAS  Google Scholar 

  10. Paulsson K, Fioretos T, Strömbeck B, Mauritzson N, Tanke HJ, Johansson B . Trisomy 8 as the sole chromosomal aberration in myelocytic malignancies: a multicolor and locus-specific fluorescence in situ hybridization study. Cancer Genet Cytogenet 2003; 140: 66–69.

    Article  CAS  Google Scholar 

  11. Leroy H, Roumier C, Huyghe P, Biggio V, Fenaux P, Preudhomme C . CEBPA point mutations in hematological malignancies. Leukemia 2005; 19: 329–334.

    Article  CAS  Google Scholar 

  12. 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 

  13. Heller A, Brecevic L, Glaser M, Loncarevic IF, Gebhart E, Claussen U et al. Trisomy 8 as the sole chromosomal aberration in myelocytic malignancies: a comprehensive molecular cytogenetic analysis reveals no cryptic aberrations. Cancer Genet Cytogenet 2003; 146: 81–83.

    Article  CAS  Google Scholar 

  14. Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowbel D et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 1998; 20: 207–211.

    Article  CAS  Google Scholar 

  15. Drazinic CM, Ercan-Sencicek AG, Gault LM, Hisama FM, Qumsiyeh MB, Nowak NJ et al. Rapid array-based genomic characterization of a subtle structural abnormality: a patient with psychosis and der(18)t(5;18)(p14.1;p11.23). Am J Med Genet 2005; 134A: 282–289.

    Article  Google Scholar 

  16. Heidenblad M, Schoenmakers EFPM, Jonson T, Gorunova L, Veltman JA, van Kessel AG et al. Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines. Cancer Res 2004; 64: 3052–3059.

    Article  CAS  Google Scholar 

  17. Cowell JK, Matsui S-I, Wang YD, LaDuca J, Conroy J, McQuaid D et al. Application of bacterial artificial chromosome array-based comparative genomic hybridization and spectral karyotyping to the analysis of glioblastoma multiforme. Cancer Genet Cytogenet 2004; 151: 36–51.

    Article  CAS  Google Scholar 

  18. Rubio-Moscardo F, Climent J, Siebert R, Piris MA, Martín-Subero JI, Nieländer I et al. Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome. Blood 2005; 105: 4445–4454.

    Article  CAS  Google Scholar 

  19. Krzywinski M, Bosdet I, Smailus D, Chiu R, Mathewson C, Wye N et al. A set of BAC clones spanning the human genome. Nucl Acids Res 2004; 32: 3651–3660.

    Article  CAS  Google Scholar 

  20. Ishkanian AS, Malloff CA, Watson SK, deLeeuw RJ, Chi B, Coe BP et al. A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet 2004; 36: 299–303.

    Article  CAS  Google Scholar 

  21. Yang YH, Dudoit S, Luu P, Lin DM, Peng V, Ngai J et al. Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucl Acids Res 2002; 30: e15.

    Article  Google Scholar 

  22. Autio R, Hautaniemi S, Kauraniemi P, Yli-Harja O, Astola J, Wolf M et al. CGH-Plotter: MATLAB toolbox for CGH-data analysis. Bioinformatics 2003; 19: 1714–1715.

    Article  CAS  Google Scholar 

  23. Saal LH, Troein C, Vallon-Christersson J, Gruvberger S, Borg Å, Peterson C . BioArray Software Environment (BASE): a platform for comprehensive management and analysis of microarray data. Genome Biol 2002; 3: software0003.

  24. The Database of Genomic Variants 2005. http://projects.tcag.ca/variation/.

  25. Kallioniemi O-P, Kallioniemi A, Piper J, Isola J, Waldman FM, Gray JW et al. Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer 1994; 10: 231–243.

    Article  CAS  Google Scholar 

  26. Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P et al. Large-scale copy number polymorphism in the human genome. Science 2004; 305: 525–528.

    Article  CAS  Google Scholar 

  27. Andreasson P, Johansson B, Arheden K, Billström R, Mitelman F, Höglund M . Deletions of CDKN1B and ETV6 in acute myeloid leukemia and myelodysplastic syndromes without cytogenetic evidence of 12p abnormalities. Genes Chromosomes Cancer 1997; 19: 77–83.

    Article  CAS  Google Scholar 

  28. Cox MC, Panetta P, Venditti A, Del Poeta G, Franchi A, Buccisano F et al. Comparison between conventional banding analysis and FISH screening with an AML-specific set of probes in 260 patients. Hematol J 2003; 4: 263–270.

    Article  CAS  Google Scholar 

  29. Gotlib J, Cools J, Malone III JM, Schrier SL, Gilliland DG, Coutré SE . The FIP1L1-PDGFRα fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood 2004; 103: 2879–2891.

    Article  CAS  Google Scholar 

  30. Marqués F, Moreau J-L, Peaucellier G, Lozano J-C, Schatt P, Picard A et al. A new subfamily of high molecular mass CDC2-related kinases with PITAI/VRE motifs. Biochem Biophys Res Commun 2000; 279: 832–837.

    Article  Google Scholar 

  31. Lim K-H, Baines AT, Fiordalisi JJ, Shipitsin M, Feig LA, Cox AD et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 2005; 7: 533–545.

    Article  CAS  Google Scholar 

  32. Shapiro MJ, Powell P, Ndubuizu A, Nzerem C, Shapiro VS . The ALX Src homology 2 domain is both necessary and sufficient to inhibit T cell receptor/CD28-mediated up-regulation of RE/AP. J Biol Chem 2004; 279: 40647–40652.

    Article  CAS  Google Scholar 

  33. Hayami Y, Iida S, Nakazawa N, Hanamura I, Kato M, Komatsu H et al. Inactivation of the E3/LAPTm5 gene by chromosomal rearrangement and DNA methylation in human multiple myeloma. Leukemia 2003; 17: 1650–1657.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Swedish Cancer Society, the Ingabritt and Arne Lundberg Foundation, and the Knut and Alice Wallenberg Foundation via the SWEGENE program.

Author information

Authors and Affiliations

  1. Department of Clinical Genetics, Lund University Hospital, Lund, Sweden

    K Paulsson, M Heidenblad, B Strömbeck, T Fioretos & B Johansson

  2. Department of Oncology, Lund University Hospital, Lund, Sweden

    J Staaf, G Jönsson & Å Borg

  3. Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden

    Å Borg

Authors
  1. K Paulsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Heidenblad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Strömbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Staaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Jönsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Å Borg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Fioretos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Johansson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Paulsson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paulsson, K., Heidenblad, M., Strömbeck, B. et al. 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, 840–846 (2006). https://doi.org/10.1038/sj.leu.2404145

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404145

Keywords

This article is cited by

Search

Advanced search

Quick links