Anomalies of chromosomes 5, 7, 11 and 17 with complex karyotype in myelodysplastic syndrome and acute myeloid leukemia patients

Complex karyotype (CK) in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is a factor of unfavorable prognosis, associated with high frequency of refractory forms and relapses. Precise identification of chromosome abnormalities in CK by conventional cytogenetic analysis (CCA) is limited due to low resolution of this method. Molecular cytogenetic techniques (FISH, mFISH, mBAND) have significantly higher sensitivity and allow to identify complex chromosome abnormalities, marker chromosomes, submicroscopic deletions and specify chromosomes breakpoints. This study included 15 MDS and 11 AML patients whose complex karyotypes were characterized by these methods. mFISH and iFISH are performed in all 26 patients, mBAND is performed in two cases. CCA revealed an average of 7 karyotype abnormalities (from 3 to 21). Structural rearrangements were found in all cases (n = 26): reciprocal translocations (38.4%), deletions (65.3%), additional chromosomal material of unknown origin (69.2%), marker chromosomes (53.8%). Numerical anomalies typical for MDS and AML (n = 26) were found: trisomy 8 (15.3%), monosomy 5 (42.3%), 7 (34.6%) and 17 (11.5%). Molecular cytogenetic analysis revealed additional chromosomal abnormalities and / or additional chromosome breakpoints in 19 cases. Translocations were found: reciprocal in 22 cases, complicated in 13 cases. In karyotype of 23 patients we found chromosome anomalies 5 (76.9%), 7 (57.6%), 11 (34.6%) and 17 (46.1%). The deletion 5q was confirmed in five cases, the deletion of 7q in one case. True monosomy 7 is confirmed in one case. On the results of molecular cytogenetic techniques in all other cases with monosomy 5, 7, and 17 revealed fragments of these chromosomes involved in translocations were combined deletions of loci 5q31, 7q31 and 17p13. All marker chromosomes and chromosomes with additional material of unknown origin were recognized as complex translocations or derivative chromosomes with breakpoints in both arms. Combination of CCA and molecular cytogenetic techniques is necessary for the complete characterization of complex karyotypes in MDS and AML and for precise for characteristic of CK in MDS and AML and determination of exact breakpoints loci of potential oncogenes and tumor suppressor genes.

МДС, ОМЛ, комплексный кариотип, FISH, mFISH, AML, Complex aberrant karyotype, FISH, MDS

1. Nybakken G E, Bagg A. The genetic basis and expanding role of molecular analysis in the diagnosis, prognosis, and therapeutic design for myelodysplastic syndromes. J Mol Diagn. 2014 Mar;16(2):145-58

2. Arber D, Orazi A, Hassrjian R. The 2016 revision to the WHO classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20).

3. Ahmad F, Dalvi R, Mandava S. Molecular characterization of complex chromosomal rearrangement: First report of novel t(7;12) (q11;q22) as part of a complex karyotype in de novo AML. Pathol Res Pract. 2014 Dec;210(12):1090-4. https://doi.org/10.1016/j.prp.2014.08.015.

4. Greenberg P, Cox C, LeBeau MM, Fenaux P et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88.

5. Greenberg P L, Tuechler H, Schanz J Et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-65. doi: 10.1182/blood-2012-03-420489.

6. Zemanova Z, Michalova K, Buryova H Et al. Involvement of deleted chromosome 5 in complex chromosomal aberrations in newly diagnosed myelodysplastic syndromes (MDS) is correlated with extremely adverse prognosis. Leuk Res. 2014 May;38(5):537-44

7. Wang S A, Abruzzo L V, Hasserjian R P et al. Myelodysplastic syndromes with deletions of chromosome 11q lack cryptic MLL rearrangement and exhibit characteristic clinicopathologic features. Leukemia Research 35 (2011) 351-357.

8. Ferrara F, Schiffer C A. Acute myeloid leukemia in adults. Lancet. 2013 Feb 9;381(9865):484-95.

9. Breems D A, Van Putten W L et al. Monosomal Karyotype in Acute Myeloid Leukemia: A Better Indicator of Poor Prognosis Than a Complex Karyotype. J Clin Oncol. 2008 Oct 10;26(29):4791-7. doi: 10.1200/JCO.2008.16.0259.

10. Renneville A, Roumier C, Biggio V Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008 May;22(5):915-31.

11. Liehr T. Fluorescence In Situ Hybridization (FISH) -Application Guide. Springer-Verlag Berlin Heidelberg. 2009, p I (16).

12. Pinheiro R F, Chauffaille M L. Comparison of I-FISH and G-banding for the detection of chromosomal abnormalities during the evolution of myelodysplastic syndrome. Braz J Med Biol Res. 2009; 42(11):1110-2.

13. Malcovati L, Hellstrоm-Lindberg E, Bowen D et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-64.

14. Speicher M R, Gwyn Ballard S, Ward D C. Karyotyping human chromosomes by combinatorial multi- fluor FISH. Nat Genet. 1996 Apr;12(4):368-75.

15. Schrоck E, du Manoir S, Veldman T et al. Multicolor spectral karyotyping of human chromosomes. Science. 1996; 273(5274):494-7.

16. Shaffer L G, McGowan-Jordan J, Schmid M. ISCN: An International System for Human Cytogenetic Nomenclature, S. Karger, Basel, Switzerland, 2013.

17. Fenaux P. Myelodysplastic syndromes: from pathogenesis and prognosis to treatment. Semin Hematol. 2004 (2 Suppl 4):6-12.

18. Navada S, Chatalbash A, Silverman L. Clinical significance of cytogenetic manifestations in myelodysplastic syndromes. LabMedicine, 2013; 44: 103-107.

19. Haase D. Cytogenetic features in myelodysplastic syndromes. Ann Hematol. 2008; 87(7): 515-26. doi: 10.1007/s00277-008-0483-y.

20. List A, Kurtin S, Roe D J Et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005; 352(6):549-57.

21. Fenaux P, Mufti G J, Hellstrom-Lindberg E et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol. 2009;10(3):223-32.

22. Volkert S, Kohlmann A, Schnittger S et al. Association of the type of 5q loss with complex karyotype, clonal evolution, TP53 mutation status, and prognosis in acute myeloid leukemia and myelodysplastic syndrome. Genes Chromosomes Cancer. 2014 May;53(5):402-10.

23. Tanke H J, Wiegant J, van Gijlswijk RP et al. New strategy for multi-color fluorescence in situ hybridization: COBRA: combined binary ratio labelling. Eur J Hum Genet. 1999; 7(1):2-11.

24. Babicka L, Ransdorfova S, Brezinova J et al. Analysis of complex chromosomal rearrangements in adult patients with MDS and AML by multicolor FISH. Leukemia Research; 31(2007): 39-47.

25. Mrоzek K. Cytogenetic, molecular genetics, and clinical characteristics of acute myeloid leukemia with a complex karyotype. Semin Oncol. 2008 Aug;35(4):365-77.

26. Andersen M, Christiansen D et al. Duplication or amplification of chromosome band 11q23, including the unrearranged MLL gene, is a recurrent abnormality in therapy-related MDS and AML, and is closely related to mutation of the TP53 gene and to previous therapy with alkylating agents. Genes Chromosomes Cancer. 2001; 31(1):33-41.

27. Sarova I, Berezinova J et al. Characterization of Chromosome 11 Breakpoints and the Areas of Deletion and Amplification in Patients with Newly Diagnosed Acute Myeloid Leukemia. Genes Chromosomes Cancer. 2013; 52:619-635

28. Tang G, DiNardo CD, Zhang L. et al. MLL gene amplification in acute myeloid leukemia and myelodysplastic syndromes is associated with characteristic clinicopathological findings and TP53 gene mutation. Hum Pathol 46(1):65-73, 1/2015. e-Pub 10/2014. PMID: 25387813.