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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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Analysis of structural chromosomal rearrangements in hematological neoplasias; Study of structural chromosomal rearrangements of cells of chronic lymphocytic leukemia after DSP30/IL2 stimulated cultivation
Hrubá, Martina ; Michalová, Kyra (advisor) ; Goetz, Petr (referee) ; Březinová, Jana (referee)
Cytogenetic analysis of cells of chronic lymphocytic leukemia (CLL) is difficult because of their low proliferative activity. To obtain sufficient number of mitoses for performing chromosomal analysis a suitable stimulation of cell division is needed. Using DSP30/IL2 stimulated cultivation 391 CLL samples were investigated in 5 years' period. The cultivation was showed to have high success rate (96%; 375/391) with also high rate of detection of pathological clones by both karyotype and metaphase FISH analyses (in 84% of samples; 329/391). Almost in half of samples (44%; 171/391) other aberrations than recurrent FISH (i.e. 13q14 deletion, trisomy 12, TP53, ATM genes deletions) were found. Also high frequency of translocations (37%; 144/391), complex karyotypes (28%; 111/391) and clonal evolution, which was detected in one third of all samples (34% of samples with presence of more than two clones; 133/391) and like a new event in disease duration even more frequently (in 39% of samples repeatedly investigated after stimulated cultivation; 21/54), was revealed. The presence of translocations, complex karyotypes and clonal evolution was associated with progressive form of disease (P 0,000003, resp. P 0,0002 and P 0,05/P 0,04). In cases of the recurrent deletions the detailed analysis of metaphase...
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Analysis of structural chromosomal rearrangements in hematological neoplasias; Study of structural chromosomal rearrangements of cells of chronic lymphocytic leukemia after DSP30/IL2 stimulated cultivation
Hrubá, Martina
Cytogenetic analysis of cells of chronic lymphocytic leukemia (CLL) is difficult because of their low proliferative activity. To obtain sufficient number of mitoses for performing chromosomal analysis a suitable stimulation of cell division is needed. Using DSP30/IL2 stimulated cultivation 391 CLL samples were investigated in 5 years' period. The cultivation was showed to have high success rate (96%; 375/391) with also high rate of detection of pathological clones by both karyotype and metaphase FISH analyses (in 84% of samples; 329/391). Almost in half of samples (44%; 171/391) other aberrations than recurrent FISH (i.e. 13q14 deletion, trisomy 12, TP53, ATM genes deletions) were found. Also high frequency of translocations (37%; 144/391), complex karyotypes (28%; 111/391) and clonal evolution, which was detected in one third of all samples (34% of samples with presence of more than two clones; 133/391) and like a new event in disease duration even more frequently (in 39% of samples repeatedly investigated after stimulated cultivation; 21/54), was revealed. The presence of translocations, complex karyotypes and clonal evolution was associated with progressive form of disease (P 0,000003, resp. P 0,0002 and P 0,05/P 0,04). In cases of the recurrent deletions the detailed analysis of metaphase...
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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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Formation of complex chromosomal rearrangements in cancer cells and significance of these events
Rochlová, Kristina ; Zemanová, Zuzana (advisor) ; Rothová, Olga (referee)
Chromoanagenesis is a catch-all term of recently described catastrophic events that generate complex karyotypes. These events are divided according to the characteristic features and are termed chromothripsis, chromoplexis and chromoanasynthesis. Chromothripsis represents a disintegration of chromosomes or their parts into hundreds of small fragments. Those chromosome fragments are then incorrectly reassembled. Chromoplexis rearrangements are not very different from chromothripsis rearrangements. The main difference is a lower number of breakpoints and the distribution of aberrations in the whole genome. The erroneous replication processes occur during chromoanasynthesis. There are several mechanisms responsible for breakdowns of a DNA molecule. In the case of chromothripsis, micronucleus formation is probably the most important mechanism. During chromoplexis, transcriptional stress plays a major role. Replication stress is associated with chromoanasynthesis rearrangements. The result of all these processes are highly rearranged chromosomes with numerous losses or gains of genetic material. This work summarizes the current knowledge of the mechanisms that are mentioned above and the genesis of complex aberrations. At the same time, it represents the connection between complex karyotype and clonal...
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Analysis of structural chromosomal rearrangements in hematological neoplasias; Study of structural chromosomal rearrangements of cells of chronic lymphocytic leukemia after DSP30/IL2 stimulated cultivation
Hrubá, Martina
Cytogenetic analysis of cells of chronic lymphocytic leukemia (CLL) is difficult because of their low proliferative activity. To obtain sufficient number of mitoses for performing chromosomal analysis a suitable stimulation of cell division is needed. Using DSP30/IL2 stimulated cultivation 391 CLL samples were investigated in 5 years' period. The cultivation was showed to have high success rate (96%; 375/391) with also high rate of detection of pathological clones by both karyotype and metaphase FISH analyses (in 84% of samples; 329/391). Almost in half of samples (44%; 171/391) other aberrations than recurrent FISH (i.e. 13q14 deletion, trisomy 12, TP53, ATM genes deletions) were found. Also high frequency of translocations (37%; 144/391), complex karyotypes (28%; 111/391) and clonal evolution, which was detected in one third of all samples (34% of samples with presence of more than two clones; 133/391) and like a new event in disease duration even more frequently (in 39% of samples repeatedly investigated after stimulated cultivation; 21/54), was revealed. The presence of translocations, complex karyotypes and clonal evolution was associated with progressive form of disease (P 0,000003, resp. P 0,0002 and P 0,05/P 0,04). In cases of the recurrent deletions the detailed analysis of metaphase...
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Analysis of structural chromosomal rearrangements in hematological neoplasias; Study of structural chromosomal rearrangements of cells of chronic lymphocytic leukemia after DSP30/IL2 stimulated cultivation
Hrubá, Martina ; Michalová, Kyra (advisor) ; Goetz, Petr (referee) ; Březinová, Jana (referee)
Cytogenetic analysis of cells of chronic lymphocytic leukemia (CLL) is difficult because of their low proliferative activity. To obtain sufficient number of mitoses for performing chromosomal analysis a suitable stimulation of cell division is needed. Using DSP30/IL2 stimulated cultivation 391 CLL samples were investigated in 5 years' period. The cultivation was showed to have high success rate (96%; 375/391) with also high rate of detection of pathological clones by both karyotype and metaphase FISH analyses (in 84% of samples; 329/391). Almost in half of samples (44%; 171/391) other aberrations than recurrent FISH (i.e. 13q14 deletion, trisomy 12, TP53, ATM genes deletions) were found. Also high frequency of translocations (37%; 144/391), complex karyotypes (28%; 111/391) and clonal evolution, which was detected in one third of all samples (34% of samples with presence of more than two clones; 133/391) and like a new event in disease duration even more frequently (in 39% of samples repeatedly investigated after stimulated cultivation; 21/54), was revealed. The presence of translocations, complex karyotypes and clonal evolution was associated with progressive form of disease (P 0,000003, resp. P 0,0002 and P 0,05/P 0,04). In cases of the recurrent deletions the detailed analysis of metaphase...
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