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Complex chromosomal aberrations in bone marrow cells of adult patients with myelodysplastic syndromes (MDS): frequency, mechanism of origin and clinical significance.
Rochlová, Kristina ; Zemanová, Zuzana (advisor) ; Novotná, Drahuše (referee)
Complex chromosomal aberrations occurs are described in approximately 20 % of patients with myelodysplastic syndrome (MDS) and are associated with a poor prognosis. Nevertheless, the mechanism and possible causes responsible for the emergence of these aberrations are not fully understood. There are two models describing the emergence of these aberrations, namely shattering of single chromosomes or their parts during the so-called cellular crisis (chromothripsis) and/or progressive accumulation of chromosomal aberrations during the course of the disease (clonal evolution). Using combination of cytogenomic methods we examined 61 samples of bone marrow from adult patients with MDS and a complex karyotype. Unbalanced aberrations with loss of genetical material were found in most cases. Chromosomes 5, 7 and 12 were most frequently involved in rearrangements. Clonal development, chromothripsis and both mechanism was detected in 26, 12 and 14 patients, respectively. Patients with deleted chromosome 5 included in complex karyotype had the shortest overall survival. The cause of emergence of complex aberrations did not affect survival. Cytogenomic analysis of complex aberrations allows detection of balanced and unbalanced changes and identification of important processes of tumorigenesis such as clonal...
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Unbalanced changes in cancer cells genome and its role in cancer pathogenesis
Lhotská, Halka ; Zemanová, Zuzana (advisor) ; Jarošová, Marie (referee) ; Kuglík, Petr (referee)
Malignant transformation of cell is characterized by genomic instability that involves unbalanced changes besides other things. We analyzed genomic aberrations, promoter methylation and mutations of several clinically relevant genes using I-FISH, mFISH, mBAND, CGH array, SNP array, MLPA, MS-MLPA and MS-PCR methods. We focused on two groups of patients well known for frequent appearance of unbalanced changes - patients with malignant brain tumors (gliomas) and patients with myelodyspastic syndromes (MDS). In patients with low grade glioma (WHO grade I - II), the codeletion of 1p/19q (82,6% oligodendrogliomas and oligoastrocytomas), mutation of IDH1/IDH2 genes (87% WHO grade I-II gliomas), copy neutral loss of heterozygozyty of 17p (72,2% astrocytomas) and higher presence of unbalanced aberration in astrocytomas belongs to the most frequent findings. We described yet unpublished methylation of MLH3 gene promoter in 60,9% oligodendrogliomas and in 27,3% astrocytomas. We also observed clonal evolution in patients with recurrent tumors. We studied secondary rearrangements of deleted chromosome 5 in patients with MDS and complex karyotype and we described its most recurrent translocation partners and breakpoints. We observed chromothripsis in 49% of these patients and it was frequently associated with...
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Clonal evolution of leukemic cells and its role in the progression of leukemia and preleukemia
Svobodová, Karla ; Zemanová, Zuzana (advisor) ; Urbánková, Helena (referee) ; Šubrt, Ivan (referee)
Clonal evolution is a multistep process characterized by progression of the disease, adverse prognosis and shortening of overall survival. The aim of the dissertation was a detailed characterization of identified changes in patients with myelodysplastic syndromes (MDS) and clonal evolution and evaluation of their prognostic impact. We performed detail cytogenomic analyses in 36/469 (8%) patients with confirmed linear clonal evolution. We described 57 primary abnormalities (32% MDS-specific) at the time of diagnosis, the most frequent was deletion of long arm of chromosome 5. We proved 156 secondary aberrations (21% MDS-specific) during the course of the clonal evolution, the most frequent were trisomies/tetrasomies of chromosome 8. We identified acquired uniparental disomies (aUPD) in 19% of patients. In MDS-specific aUPDs 4q, 11q and 17p, we proved homozygous mutations of TET2, c-CBL and TP53 genes. We found a statistically significant difference in overall survival between the groups of patients divided according to their diagnostic cytogenomic findings. In patients with clonal evolution before treatment 54% of aberrations were gains of whole chromosomes, by contrast 44% of abnormalities identified in patients with clonal evolution after treatment were monosomies or deletions. The study of clonal...
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The aberration of chromosome 7 in haematological malignancies of the myeloid lineage
Onderková, Martina ; Ransdorfová, Šárka (advisor) ; Froňková, Eva (referee)
Accurate localization of breakpoints and deleted regions on chromosome 7 in bone marrow cells of patients is an essential step in identifying genes involved in tumor transformation of a cell. In case of hematological malignancies usually oncogenes and tumor suppressor genes are activated or deleted by a change in the arrangement of genetic material. Aberration of chromosome 7, total or partial loss of chromosome, especially long arms 7q, are among the recurrent cytogenetic abnormalities in patients with myeloid diseases such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Aberrations of chromosome 7 are an important prognostic marker occurring in 8-10% de novo MDS and AML and in 40-50% treated MDS / AML. For a detailed analysis of chromosome 7 breakpoints and aberrations, samples of 51 adult patients diagnosed with AML / MDS were examined using conventional and molecular cytogenomic methods. In our testing group we demonstrated a separate 7q deletion in one patient (2%) and an isolated monosomy of chromosome 7 in six patients (12%). Aberration of chromosome 7 detected in combination with another change was found in 17 cases (33%) and 27 patients (53%) had complex karyotype changes including chromosome 7. The most frequent breakpoint was 7q22. In 26 patients we proved a deletion...
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Unbalanced changes in cancer cells genome and its role in cancer pathogenesis
Lhotská, Halka ; Zemanová, Zuzana (advisor) ; Jarošová, Marie (referee) ; Kuglík, Petr (referee)
Malignant transformation of cell is characterized by genomic instability that involves unbalanced changes besides other things. We analyzed genomic aberrations, promoter methylation and mutations of several clinically relevant genes using I-FISH, mFISH, mBAND, CGH array, SNP array, MLPA, MS-MLPA and MS-PCR methods. We focused on two groups of patients well known for frequent appearance of unbalanced changes - patients with malignant brain tumors (gliomas) and patients with myelodyspastic syndromes (MDS). In patients with low grade glioma (WHO grade I - II), the codeletion of 1p/19q (82,6% oligodendrogliomas and oligoastrocytomas), mutation of IDH1/IDH2 genes (87% WHO grade I-II gliomas), copy neutral loss of heterozygozyty of 17p (72,2% astrocytomas) and higher presence of unbalanced aberration in astrocytomas belongs to the most frequent findings. We described yet unpublished methylation of MLH3 gene promoter in 60,9% oligodendrogliomas and in 27,3% astrocytomas. We also observed clonal evolution in patients with recurrent tumors. We studied secondary rearrangements of deleted chromosome 5 in patients with MDS and complex karyotype and we described its most recurrent translocation partners and breakpoints. We observed chromothripsis in 49% of these patients and it was frequently associated with...
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