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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 changes in expression of long non-coding RNAs in hepatocellular carcinoma
Krhutová, Magdaléna ; Pávek, Petr (advisor) ; Matoušková, Petra (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Bc. Magdaléna Krhutová Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: The changes in expression of long non-coding RNAs in hepatocellular carcinoma Hepatocellular carcinoma (HCC) is one of the highly prevalent cancers globally. A number of new cases of HCC and deaths rises every year. Molecular mechanisms of HCC are being intensively studied, yet they are not still fully understood. In addition to genetic alterations, epigenetics also plays an important role in HCC pathogenesis. Long non- coding RNAs (lncRNAs) are RNA molecules that are not capable of coding proteins, and their length is 200 nucleotides or more. Various studies have already revealed lncRNAs involved in tumorigenesis through binding to DNA, RNA and proteins. New studies also demonstrate significant changes in the expression of biotransformation enzymes in HCC, and interactions with microRNAs (miRNAs) and lncRNAs. This diploma thesis deals with the issue of long non-coding RNAs in relation to HCC. It summarizes the epidemiological situation, risk factors, and current possibilities of diagnosis and therapy of this disease. It also summarizes recently described genetic and epigenetic mechanisms contributing...
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Characterization of hapt oglobin glycoforms in human serum
Darebná, Petra ; Pompach, Petr (advisor) ; Ptáčková, Renata (referee)
Characterization of haptoglobin glycoforms in human serum Petra Darebná (Katedra biochemie, Přírodovědecká fakulta, Univerzita Karlova v Praze, Česká republika) Changes in glycosylation of proteins are associated with several types of cancer, including hepatocelular carcinoma and colorectal carcinoma. This project deals with data independent analysis using ion cyclotron resonance with Fourier transform and tandem mass spectrometry with liquid chromatogramy and multiple reaction monitoring to quantify these changes in hepatocelular cancinoma and colorectal carcinoma with liver metastases. In the first part of the project the haptoglobin was enriched from pooled serum samples of pacients with hepatocellular carcinoma, colorectal cancer and colorectal carcinoma with metastases using hemoglobin immobilized on CNBr-activated Sepharose 4B and then purified by high pressure liquid chromatography. Individual haptoglobin glycopeptides were analyzed using ion cyclotron resonance with Fourier transform. In the second part of the project we analyzed changes in glycosylation depending on diferent tumor diseases in partially depleted serum of individual patients using ethanol precipitation. Individual fucosylated glycoforms of N-glycopeptides of serum proteins were compared with their nonfucosylated forms. In...
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The role of oxidative stress in hepatocarcinogenesis.
Kubíčková, Kristýna ; Vítek, Libor (advisor) ; Zelenka, Jaroslav (referee) ; Fraňková, Soňa (referee)
This thesis focuses on the importance of heme catabolic pathway in hepatic carcinogenesis. Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumour. It is primarily caused by hepatic cirrhosis or chronic viral hepatitis. Hepatic carcinogenesis is associated with increased oxidative stress. Thus, our study aimed to assess the expression of the genes involved in the homeostasis of oxidative stress in patients with HCC. The study was performed on patients with primary HCC (n = 29) and control subjects (n = 11), gene expressions of heme oxygenase 1 (HMOX1), biliverdin reductase A/B (BLVRA/B), endothelial growth factor (VEGFA), NADPH oxidase 2 (NOX2) and p22phox were analyzed in the liver tissue; the identical gene expressions were analyzed in peripheral blood leukocytes (PBL) in HCC patients (n = 32) and in healthy controls (n = 27). Expression of BLVRA in liver tissue and PBL was significantly increased in cancer patients, as was NOX2 expression in PBL. Expression of VEGFA in liver tissue and PBL was significantly decreased in cancer patients. The expression of the other genes studied did not differ between HCC patients and controls. These data are consistent with the results of our previous study on patients with chronic hepatitis C, in which BLVRA expression was also...
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The changes in expression of long non-coding RNAs in hepatocellular carcinoma
Krhutová, Magdaléna ; Pávek, Petr (advisor) ; Matoušková, Petra (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Bc. Magdaléna Krhutová Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: The changes in expression of long non-coding RNAs in hepatocellular carcinoma Hepatocellular carcinoma (HCC) is one of the highly prevalent cancers globally. A number of new cases of HCC and deaths rises every year. Molecular mechanisms of HCC are being intensively studied, yet they are not still fully understood. In addition to genetic alterations, epigenetics also plays an important role in HCC pathogenesis. Long non- coding RNAs (lncRNAs) are RNA molecules that are not capable of coding proteins, and their length is 200 nucleotides or more. Various studies have already revealed lncRNAs involved in tumorigenesis through binding to DNA, RNA and proteins. New studies also demonstrate significant changes in the expression of biotransformation enzymes in HCC, and interactions with microRNAs (miRNAs) and lncRNAs. This diploma thesis deals with the issue of long non-coding RNAs in relation to HCC. It summarizes the epidemiological situation, risk factors, and current possibilities of diagnosis and therapy of this disease. It also summarizes recently described genetic and epigenetic mechanisms contributing...
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Characterization of hapt oglobin glycoforms in human serum
Darebná, Petra ; Pompach, Petr (advisor) ; Ptáčková, Renata (referee)
Characterization of haptoglobin glycoforms in human serum Petra Darebná (Katedra biochemie, Přírodovědecká fakulta, Univerzita Karlova v Praze, Česká republika) Changes in glycosylation of proteins are associated with several types of cancer, including hepatocelular carcinoma and colorectal carcinoma. This project deals with data independent analysis using ion cyclotron resonance with Fourier transform and tandem mass spectrometry with liquid chromatogramy and multiple reaction monitoring to quantify these changes in hepatocelular cancinoma and colorectal carcinoma with liver metastases. In the first part of the project the haptoglobin was enriched from pooled serum samples of pacients with hepatocellular carcinoma, colorectal cancer and colorectal carcinoma with metastases using hemoglobin immobilized on CNBr-activated Sepharose 4B and then purified by high pressure liquid chromatography. Individual haptoglobin glycopeptides were analyzed using ion cyclotron resonance with Fourier transform. In the second part of the project we analyzed changes in glycosylation depending on diferent tumor diseases in partially depleted serum of individual patients using ethanol precipitation. Individual fucosylated glycoforms of N-glycopeptides of serum proteins were compared with their nonfucosylated forms. In...
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