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The role of TGFß and study of prognostic factors of patients with MDS and AML
Provazníková, Dana ; Fuchs, Ota (advisor) ; Pohlreich, Petr (referee) ; Martásek, Pavel (referee)
We did not find mutation in coding areas of genes for components of TGFbeta1 signaling pathway but we detected decreased or undetectable expression of these analysed genes.The decreased expression is probably caused by epigenetic changes, so by hypermethylation and deacetylation of promoter regionsof these genes.Antiproliferative and apoptotic effect of TGF1 was analysed in AML cell lines (ML1, ML2, CTV1 and Kasumi1). ML2 cells rezistence to inhibition of DNA synthesis by TGFβ1 is not caused by mutations of genes for components of TGFβ1 signaling pathway. We found that increased SnoN (Ski-like novel gene) expression on the level of coresponding mRNA and protein is probably accountable for this rezistence. Kasumi1 and M2 cells were sensitive to induction of apoptózis caused by TGFβ1 treatment but in less extent than by proteazome inhibitor bortezomib. The difference of AML cells of different lines answers shows a great heterogeneity AML in AML patients. Prognostic factors analysis in AML with normal karyotype confirmed that CEBPA (CCAAT/enhancer binding protein alpha) mutations predict favourable prognosis but the elevated EVI1 ("Ecotropic Virus Integration Site 1") and ERG ("ETS-related gene") expression are connected with unfavourable prognosis. EVI1 is a negative marker for MDS as well. We did not confirm...
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The role of TGFß and study of prognostic factors of patients with MDS and AML
Provazníková, Dana ; Fuchs, Ota (advisor) ; Pohlreich, Petr (referee) ; Martásek, Pavel (referee)
We did not find mutation in coding areas of genes for components of TGFbeta1 signaling pathway but we detected decreased or undetectable expression of these analysed genes.The decreased expression is probably caused by epigenetic changes, so by hypermethylation and deacetylation of promoter regionsof these genes.Antiproliferative and apoptotic effect of TGF1 was analysed in AML cell lines (ML1, ML2, CTV1 and Kasumi1). ML2 cells rezistence to inhibition of DNA synthesis by TGFβ1 is not caused by mutations of genes for components of TGFβ1 signaling pathway. We found that increased SnoN (Ski-like novel gene) expression on the level of coresponding mRNA and protein is probably accountable for this rezistence. Kasumi1 and M2 cells were sensitive to induction of apoptózis caused by TGFβ1 treatment but in less extent than by proteazome inhibitor bortezomib. The difference of AML cells of different lines answers shows a great heterogeneity AML in AML patients. Prognostic factors analysis in AML with normal karyotype confirmed that CEBPA (CCAAT/enhancer binding protein alpha) mutations predict favourable prognosis but the elevated EVI1 ("Ecotropic Virus Integration Site 1") and ERG ("ETS-related gene") expression are connected with unfavourable prognosis. EVI1 is a negative marker for MDS as well. We did not confirm...
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Genetic factors responsible for hereditary breast and ovarian cancer development Large rearrangements in BRCA1 and BRCA2 genes
Tichá, Ivana ; Pohlreich, Petr (advisor) ; Souček, Pavel (referee) ; Stiborová, Marie (referee)
2. Summary Background: A greatly increased risk for development of hereditary breast cancer is associated with germline mutations in several susceptibility genes. In this study we analyzed large genomic rearrangements (LGRs) in BRCA1/2 genes and we also focused on the role of CHEK2 and TP53 in tumorigenesis. Methods: A series of 586 high risk patients with breast/ovarian cancer that had previously been tested negatively for small mutations in BRCA1/2 was screened for LGRs by MLPA, LR-PCR and sequencing. Chromosome 17-specific aCGH was used to locate deletion breakpoints in regions flanking the BRCA1 gene. MLPA-analysis was also used to detect two frequently occurring mutations in CHEK2 (c.1100delC and a deletion of 5395 bp). The coding region of the TP53 gene was analyzed by sequencing. Results: We identified 9 different LGRs in the BRCA1 gene in 16 patients. Five alterations (deletion of exons 1-17, 5-10, 13-19, 18-22 and 21-24) were novel. Deletions of exons 1-17, 5-14 and 21-22 were identified repeatedly, and represented population specific (founder) mutations. LGRs accounted for 12.1% (16/132) of all detected pathogenic BRCA1 mutations. No LGRs were found in the BRCA2 gene. Pathogenic mutations in other tested genes were less frequent; 2 were detected in TP53 and 9 in CHEK2. Conclusions: In our...
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The role of ATM in breast cancer
Soukupová, Jana ; Pohlreich, Petr (advisor) ; Souček, Pavel (referee) ; Foretová, Lenka (referee)
Incidence of breast cancer is continuously increasing in the Czech Republic. Tumor development is a result of gene alterations'accumulation, particulary associated with genes involved in regulation of cell growth and division. Hereditary carcinomas account for approximately 5-10% of all breast tumors and in 60-80% cases are caused by a germline mutation in the major predisposition genes BRCA1 and BRCA2. Nevertheless, other genes, mostly of lower penetrance, may play a role in breast pathogenesis such as the ATM tumor-suppressor gene. ATM is the apex of the repair pathway of DSB. This protein kinase activates through phosphorylation of its substrates cell cycle checkpoints, which leads either to the delay of the cell cycle progression until DSB are repaired or to the promotion of apoptosis. To sum up, the ATM gene seems to have a role in breast cancer development in a minority of the high-risk families in our population which is significantly lower compared to BRCA1/2 and it also seems to be involved in pathogenesis of sporadic breast cancer. Despite the ATM gene's length, we do not perform the preventive screening of this gene in breast cancer high-risk families. Nevertheless, we offer the molecular diagnostics of ATM to ataxia telangiectasia patients.
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