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

Overview

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


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Haematology Internal medicine Clinical oncology
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