Acquired uniparental disomy in bone-marrow cells of patients with myelodysplastic syndrome and complex karyotype

Authors: K. Svobodová 1;  Z. Zemanová 1;  H. Lhotská 1;  M. Nováková 1;  J. Březinová 2;  M. Beličková 2;  A. Berková 1;  I. Šárová 2;  L. Lizcová 1;  S. Izáková 1;  A. Jonášová 3;  J. Čermák 2;  K. Michalová 1,2
Authors‘ workplace: Centrum nádorové cytogenetiky, Ústav lékařské biochemie a laboratorní diagnostiky, VFN a 1. LF UK, Praha 1;  Ústav hematologie a krevní transfuze, Praha 2;  I. interní klinika, VFN a 1. LF UK, Praha 3
Published in: Transfuze Hematol. dnes,21, 2015, No. 3, p. 126-134.
Category: Comprehensive Reports, Original Papers, Case Reports


Complex karyotypes are seen in approximately 20% of patients with myelodysplastic syndromes (MDS) and are associated with a high risk of transformation into acute myeloid leukaemia (AML) and poor prognosis. Acquired uniparental disomy (aUPD, i.e. both copies of a chromosome pair or its part originate from one parent) may contribute to increased genomic instability in bone-marrow cells of patients with MDS. The pathological potential of aUPD, which arises as a clonal aberration in a proportion of somatic cells, involves tumour suppressor gene and oncogene homozygous mutations.

The aim of this study was to evaluate the frequency and implications of uniparental disomy (UPD) in a cohort of 57 patients with MDS and complex karyotype using array comparative genomic hybridization with detection of single nucleotide polymorphisms (aCGH/SNP).

UPD was found to be present in 40 regions in 21 of 57 patients (36.8%). Almost half of these involved non-recurrent changes (19/40). Chromosome X UPD was detected in six patients (Xp22.11–Xp22.2 in four and Xq13.3–Xq21.1 in two, respectively). UPD of 17q with a variable extent from 17q22 to 17q24.2 was observed in two patients. The most common finding was aUPD of the short arm of chromosome 17, which was detected in 13 of 57 patients (22.8%). Mutational analysis confirmed a homozygous mutation of the TP53 gene in all samples with this finding, including two frameshift mutations that are not registered in the IARC (International Agency for Research on Cancer TP53) database. This finding correlated with very poor prognosis (median OS 4 months). aUPD 17p was strongly associated with complex karyotype in the studied cohort. However, other previously published aUPDs in MDS (1p, 4q, 7q, 11q, 13q, 21q) were not found in our study.

UPD regions appear to be balanced (i.e. without change of DNA copies) by conventional and molecular cytogenetic methods. Therefore, aCGH/SNP represents an ideal method for the identification and further characterization of UPDs and affected genes significant for disease development and progression.

Key words:
uniparental disomy, myelodysplastic syndromes, complex karyotype, mutation, TP53 gene


1. Schoch C, Haferlach T, Bursch S, et al. Loss of genetic material is more common than gain in acute myeloid leukemia with complex aberrant karyotype: a detailed analysis of 125 cases using conventional chromosome analysis and fluorescence in situ hybridization including 24-color FISH. Genes Chromosomes Cancer, 2002;35(1):20–29.

2. Tuna M, Knuutila S, Mills GB. Uniparental disomy in cancer. Trends Mol Med, 2009;15(3):120–128.

3. Kralovics R, Guan Y, Prchal JT. Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol, 2002;30:229–236.

4. Kralovics R, Buser AS, Teo S, et al. Comparison of molecular markers in a cohort of patients with chronic myeloproliferative disorders. Blood, 2003;102(5):1869–1871.

5. Kralovics R, Passamonti F, Buser AS. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med, 2005;352:1779–1790.

6. Makishima H, Maciejewski JP. Pathogenesis and consequences of uniparental disomy in cancer. Clin Cancer Res, 2011;17:3913–3923.

7. O’Keefe C, McDevitt MA, Maciejewski JP. Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies. Blood, 2010;115(14):2731–2739.

8. Dunbar AJ, Gondek LP, O’Keefe C, et al. 250K SNP array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res, 2008;68(24):10349–10357.

9. Szpurka H, Gondek LP, Mohan SR, Hsi ED, Theil KS, Maciejewski JP. UPD1p indicates the presence of MPL W515L mutation in RARS-T, a mechanism analogous to UPD9p and JAK2 V617F mutation. Leukemia, 2009;23:610–614.

10. Jankowska AM, Szpurka H, Tiu RV, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood, 2009;113(25):6403–6410.

11. Langemeijer SMC, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet, 2009;41(7):838–842.

12. Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet, 2010;42(8):722–726.

13. Fitzgibbon J, Smith L-L, Raghavan M. Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias. Cancer Res, 2005;65:9152–9154.

14. Jasek M, Gondek LP, Bejanyan N, et al. TP53 mutations in myeloid malignancies are either homozygous or hemizygous due to copy number-neutral loss of heterozygosity or deletion of 17p. Leukemia, 2010;24(1):216–219.

15. Score J, Cross NCP. Acquired uniparental disomy in myeloproliferative neoplasms. Hematol Oncol Clin N Am, 2012;26:981–991.

16. Swerdlow S H, Campo E, Harris N L, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France. IARC Press 2008.

17. Shaffer LG, McGowan-Jordan J, Schmid M (eds). ISCN 2013: An International System for Human Cytogenetic Nomenclature. S. Karger, Basel 2013.

18. Ikeda M, Ishida O, Hinoi T, Kishida S, Kikuchi A. Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral. J Biol Chem, 1998;273:814–821.

19. Ooosterhoff JK, Penninkhof F, Brinkmann AO, Grootegoed JA, Blok LJ. REPS2/POB1 is downregulated during human prostate cancer progression and inhibits growth factor signalling in prostate cancer cells. Oncogene, 2003;22:2920–2925.

20. Boultwood J, Pellagatti A, Nikpour M, et al. The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts. PLoS ONE, 2008;3(4):1970.

21. D‘Hooghe M, Selleslag D, Mortier G, et al. X-linked sideroblastic anemia and ataxia: a new family with identification of a fourth ABCB7 gene mutation. Eur J Paediatr Neurol, 2012;16:730–735.

22. Nikpour M, Scharenberg C, Liu A, et al. The transporter ABCB7 is mediator of the phenotype of acquired refractory anemia with ring sideroblasts. Leukemia, 2013;27:889–896.

23. Levitus M, Waisfisz Q, Godthelp BC, et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group. J Nat Genet, 2005;37:934–935.

24. Cantor SB, Bell DW, Ganesan S, et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell, 2001;105:149–160.

25. Ren LP, Xian YS, Diao DM, Chen Y, Guo Q, Dang CX. Further evidence for the contribution of the BRCA1-interacting protein-terminal helicase 1 (BRIP1) gene in breast cancer suspectibility. Genet Mol Res, 2013;12(4):5793–5801.

26. Wu Z, Brabletz T, Fearon E. Canonical Wnt suppressor, Axin2, promotes colon carcinoma oncogenic aktivity. Proc Natl Acad Sci USA, 2012;109(28):11312–11317.

27. Tiu RV, Gondek LP, O’Keefe C, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood, 2011;117(17):4552–4560.

Haematology Internal medicine Clinical oncology
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account