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Sequence variants in metastatic colorectal cancer and their evolution during the disease course and treatment
Jandová, Eliška ; Boublíková, Ludmila (advisor) ; Vymetálková, Veronika (referee)
A deeper understanding of the molecular background of colorectal cancer (CRC) can help explain the development of the disease and its resistance to treatment, predict disease progression, and improve treatment prognosis. Some minimal molecular testing has been incorporated into standard clinical management to determine if a particular patient will benefit from a particular therapy, but more and more new genetic alterations are being discovered that appear to be associated with the development of resistance. Tissue biopsy of the tumor is the gold standard in terms of molecular testing, but there is an increasing demand for more non- invasive methods such as liquid biopsy. Using targeted next-generation sequencing, we analyzed sequence variants present in primary tumor, metastases, and cell-free tumor DNA - ctDNA of patients with metastatic CRC. The objectives were to analyze sequence variants of the primary tumor and identify possible pathogenic variants, to analyze differences between DNA of the primary tumor and metastases, to evaluate the use of ctDNA as a diagnostic tool, and to identify potential tumor-specific markers in ctDNA that can be used to monitor disease progression. Our results suggest the feasibility of using ctDNA for diagnostic purposes or even to monitor disease progression, but...
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Circulating biomarkers in colorectal cancer and their application in diagnosis and prognosis
Červená, Klára ; Vymetálková, Veronika (advisor) ; Boublíková, Ludmila (referee) ; Václavíková, Radka (referee)
Despite all the advances in the field of clinical and molecular oncology, the numbers related to the incidence and mortality of colorectal cancer (CRC) remain at unacceptable levels. In recent years, liquid biopsy consisting of circulating biomarkers has come to the forefront of research, offering many advantages over conventional biopsy, such as providing timely information on tumor heterogeneity and the ease of repeated sampling. This dissertation thesis aimed to identify novel candidate circulating biomarkers from microRNAs, long non-coding RNAs, and cell-free DNA that could be used for earlier diagnosis, better prognosis, or prediction of therapy response of CRC patients and thus further advance personalized medicine. The main results of this work are: 1) Circulating microRNAs in plasma (miR-122-5p and miR- 142-5p) can distinguish patients with rectal cancer and cancer-free individuals and could predict therapy response in patients (both in primary and metastatic CRC patients). 2) Gene amplification of the long non-coding RNA MALAT1 can represent an important step in the transition of healthy mucosa to adenoma tissue. Plasma MALAT1 is overexpressed in patients with colorectal adenomas and CRC patients compared to cancer-free individuals and has the potential as a predictive biomarker for CRC...
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Clinico-pathological characteristics of mucin-producing colorectal carcinoma
Sojka, Ladislav ; Levý, Miroslav (advisor) ; Boublíková, Ludmila (referee) ; Klos, Dušan (referee)
Colorectal carcinoma (CRC) is one of the most common malignancies worldwide with persistently high mortality. As a consequence, high demands are placed on research into this disease. The aim of this study was to evaluate the epidemiology of colorectal carcinoma in the Czech Republic in comparison with worldwide data. We focused on the evaluation of the latest findings in screening and diagnosis, investigated prognostic factors, and also focused on the therapeutic options of CRC. Furthermore, mucin-producing carcinomas are described in detail and mucin itself was confirmed as a risk factor for the prognosis of CRC patients. The experimental part of the study focused on gene mucin MUC13 and the MUC13 - miR-4647 axis, which is associated with adverse prognosis in CRC patients. Samples of CRC and samples of adjacent non-malignant mucosa tissue were used. The samples were collected from patients who underwent surgery at the General University Hospital in Prague, at the Thomayer University Hospital in Prague and at the University Hospital in Pilsen (Czech Republic). The collection of samples took place between 2011 and 2015. The total of 187 samples were collected from patients with sporadic colorectal cancer. The subjects of the study all provided information on their lifestyle habits, body mass index...
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Molecular aberrations in testicular germ cell tumors and their significance in tumor pathogenesis and clinical practice
Matoušková, Laura ; Boublíková, Ludmila (advisor) ; Vymetálková, Veronika (referee)
Testicular germ cell tumors (TGCT) are rare in general but they are also the most commonly occuring malignant tumors in adolescent and young males. Predispositions for the incidence of TGCT include genetic factors - a number of discovered DNA risk loci, epigenetic changes in DNA, alterations of various signaling pathways and also external environmental risk factors. These tumors usually respond to cisplatine therapy very well, nevertheless some patients develop a resistance to this cytostatic medicament. There is still relatively small amount of research dedicated to the cause of cisplatine resistance, as well as to bio-molecular characteristics of TGCT and their role in the pathogenesis. As a result, there is only a little development in TGCT therapy to this day and thus there is no targeted therapy available, which would be highly effective for treating patients with developed cisplatine resistance and/or poor prognosis of their disease. As a result of the fact that TGCT incidence is increasing in the recent decades, it can be considered an actual problem requiring urgent addressing in order to improve the survival rate and quality of life of patients with advanced TGCT. Theoretical part of this thesis deals with the main currently known molecular characteristics of TGCT as well as cisplatine...
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The role of WT1 gene and other molecular biological abnormalities in testicular germ cell tumors
Bakardjieva - Mihaylova, Violeta ; Boublíková, Ludmila (advisor) ; Chovanec, Michal (referee) ; Kiss, Igor (referee)
Testicular germinal tumors (TGCT) are relatively rare solid tumors in adults. Even so, they affect more than 700 men a year in the Czech Republic, mostly young patients aged 18- 45 years. A large number of patients are curable by a combination of surgery and chemotherapy, yet about 50 men a year in the Czech Republic succumb to this tumor, in the vast majority of cases due to the development of resistance to chemotherapy containing cisplatin. The rare occurrence and high curability are probably the cause of infrequent molecular and clinical studies carried out in these tumors, and our understanding of the biological processes leading to primary tumor development and the development of cisplatin resistance (CDDP) is still limited. At present, no specific molecular markers that could be used as prognostic or predictive factors and improve patient stratification or treatment tailoring are available in TGCT management. In this work, we studied the molecular-genetic background of TGCT development and CDDP resistance at several levels. To comprehensively study the development of cisplatin resistance, we prepared and analyzed CDDP-exposed TGCT cell lines. Long-term exposure to CDDP increased resistance 10-fold in the NCCIT cell line, while no significant resistance was achieved with Tera-2. The...
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The role of WT1 gene and other molecular biological abnormalities in testicular germ cell tumors
Bakardjieva - Mihaylova, Violeta ; Boublíková, Ludmila (advisor) ; Chovanec, Michal (referee) ; Kiss, Igor (referee)
Testicular germinal tumors (TGCT) are relatively rare solid tumors in adults. Even so, they affect more than 700 men a year in the Czech Republic, mostly young patients aged 18- 45 years. A large number of patients are curable by a combination of surgery and chemotherapy, yet about 50 men a year in the Czech Republic succumb to this tumor, in the vast majority of cases due to the development of resistance to chemotherapy containing cisplatin. The rare occurrence and high curability are probably the cause of infrequent molecular and clinical studies carried out in these tumors, and our understanding of the biological processes leading to primary tumor development and the development of cisplatin resistance (CDDP) is still limited. At present, no specific molecular markers that could be used as prognostic or predictive factors and improve patient stratification or treatment tailoring are available in TGCT management. In this work, we studied the molecular-genetic background of TGCT development and CDDP resistance at several levels. To comprehensively study the development of cisplatin resistance, we prepared and analyzed CDDP-exposed TGCT cell lines. Long-term exposure to CDDP increased resistance 10-fold in the NCCIT cell line, while no significant resistance was achieved with Tera-2. The...
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