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Characterization of germline alterations affecting genes influencing development and prognosis of specific adult cancers
Jelínková, Sandra ; Kleibl, Zdeněk (advisor) ; Hlaváč, Viktor (referee) ; Hájková, Nikola (referee)
In my dissertation, I studied the genetic predisposition of selected types of cancer that have not been systematically studied in the Czech Republic. We used next-generation panel sequencing to identify germline pathogenic variants. Analysis of 1333 patients with ovarian cancer, 527 patients with endometrial cancer, and 334 patients with hepatocellular carcinoma included sequencing using the CZECANCA panel. A specific CZMELAC panel was prepared for the analysis of 264 melanoma patients. We focused on the identification of pathogenic variants in known predisposition genes. We also evaluated candidate genes and phenotypic characteristics in carriers of pathogenic variants. Analysis of high-risk melanoma patients revealed pathogenic variants in melanoma associated genes in 9/264 (3.4%) patients, and an additional 22 (8.3%) patients carried a pathogenic variant in one of the other predisposition genes. The odds of carrying a pathogenic variant were increased in probands with multiple melanomas and in the presence of melanoma in relatives. The incidence of germline pathogenic variants was highest in ovarian cancer, where pathogenic variants were found in 427/1332 (32.0%) patients, with a predominance of mutations in BRCA1, BRCA2, followed by alterations in other ovarian predisposition genes. Breast and...
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The effect of maternal nutrition on the newborn genome methylation
Pavlíková, Jitka ; Rössner, Pavel (advisor) ; Černá, Marie (referee) ; Hlaváč, Viktor (referee)
The maternal diet during pregnancy is an important factor involved in the epigenetic programming of the offspring. In addition to the nutritional aspect, the epigenome is also influenced by possible contaminating substances that may occur in the diet of pregnant women. An important group of these potential contaminants are persistent organic pollutants, which are compounds of mostly anthropogenic origin that persist in the environment for a long time, become part of food chains, and some of them accumulate in living organisms. These substances are being monitored for their adverse effects on organisms, and the use of some of them has already been banned or at least significantly restricted. The aim of this work was to find out whether the quality of the diet of pregnant women in the Czech Republic differs in terms of nutrition and contamination with persistent organic pollutants so much that these differences can be reflected in the methylome of newborns. The diet quality of 49 pregnant women from the Karviná and České Budějovice regions was analyzed. During the last month of pregnancy, these women recorded in detail all the food they ate for one week and at the same time collected a quarter of this food in boxes (one box for one day). Information on the quantity and quality of the diet was...
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The role of circulating microRNAs in the therapy response prediction in colorectal cancer patients.
Landecká, Aneta ; Vymetálková, Veronika (advisor) ; Hlaváč, Viktor (referee)
Colorectal cancer (CRC) is one of the most common cancers both in the world and in the Czech Republic. Predispositions for the development of CRC include genetic and epigenetic changes, as well as environmental and microenvironmental factors. These tumours often respond very well to treatment, especially in the early stages, but some patients experience early recurrence of the disease. As the incidence of CRC has not declined in recent years, this is a current problem requiring a new approach aimed at improving diagnosis, survival and quality of life of patients with CRC. For this reason, liquid biopsy, which is a minimally invasive approach to the patient and allows real-time monitoring of changes in the body, is increasingly gaining prominence. One of the biomarkers that can be detected by liquid biopsy are small non-coding RNA molecules - microRNAs (miRNAs). In this thesis, the gene expression of two miRNAs, namely miR-122-5p and miR-142-5p, was analyzed in plasma and tissues of CRC patients and in plasma of a control group of healthy blood donors. In our study, we identified significant changes in the expression levels of both miRNAs in CRC patients compared to healthy cancer- free subjects. Specifically, higher expression levels of both miRNAs were observed in CRC patients compared to the...
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The role of genetic factors in the prognosis and prediction of effects of the chemotherapy of breast carcinoma
Hlaváč, Viktor ; Souček, Pavel (advisor) ; Hodek, Petr (referee) ; Liška, Václav (referee)
Breast carcinoma is the most common cancer among women in our country and worldwide. One of the obstacles to successful therapy is a multidrug resistance. It can be caused by different factors, such as overexpression of ABC transporters, or decreased expression of SLC transporters, deregulation of drug metabolizing enzymes, variability of the targets of anticancer drugs, failure of apoptosis or increased capacity of repair genes. The aim of this study was to search for associations of genes of drug transport and metabolism with the prognosis of patients or response to chemotherapy. From the view of preventive medicine, this aim constitutes an important part of both secondary and tertiary prevention of cancer, i.e., discovery of markers enabling optimal therapy selection for each patient, decreasing the risk of disease progression to advanced and resistant stage, and elimination of side effects of chemotherapy. The expression profile of ATP-binding cassette (ABC) transporters (49 genes), cytochromes P450 (CYPs, 10 genes), aldo-keto reductases (AKRs, 13 genes) and carbonyl reductase 1 was analyzed in the tumor and adjacent non- tumor control tissues in a cohort of neoadjuvantly treated patients. Genes deregulated in tumors compared with control tissues or genes associated with clinical data were assessed in...
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The role of genetic factors in the prognosis and prediction of effects of the chemotherapy of breast carcinoma
Hlaváč, Viktor ; Souček, Pavel (advisor) ; Hodek, Petr (referee) ; Liška, Václav (referee)
Breast carcinoma is the most common cancer among women in our country and worldwide. One of the obstacles to successful therapy is a multidrug resistance. It can be caused by different factors, such as overexpression of ABC transporters, or decreased expression of SLC transporters, deregulation of drug metabolizing enzymes, variability of the targets of anticancer drugs, failure of apoptosis or increased capacity of repair genes. The aim of this study was to search for associations of genes of drug transport and metabolism with the prognosis of patients or response to chemotherapy. From the view of preventive medicine, this aim constitutes an important part of both secondary and tertiary prevention of cancer, i.e., discovery of markers enabling optimal therapy selection for each patient, decreasing the risk of disease progression to advanced and resistant stage, and elimination of side effects of chemotherapy. The expression profile of ATP-binding cassette (ABC) transporters (49 genes), cytochromes P450 (CYPs, 10 genes), aldo-keto reductases (AKRs, 13 genes) and carbonyl reductase 1 was analyzed in the tumor and adjacent non- tumor control tissues in a cohort of neoadjuvantly treated patients. Genes deregulated in tumors compared with control tissues or genes associated with clinical data were assessed in...
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