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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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Identification of hereditary factors influencing the formation of a pancreatic carcinoma and other solid tumours
Král, Jan ; Janatová, Markéta (advisor) ; Hojný, Jan (referee) ; Šeborová, Karolína (referee)
Pancreatic adenocarcinoma (PDAC) has one of the worst prognoses out of all cancers worldwide. Endometrial carcinoma (EC) is the most common gynecological cancer. Genetic background of tumors is highly heterogenous and differs among populations. We have analyzed DNA of 226 PDAC patients and 527 EC patients using panel next- generation sequencing. Targeted genes were divided into main predisposition genes (11 for PDAC, 19 for EC) and other candidate genes. EC patients were categorized based on meeting the indication criteria for germline genetic testing. Two sets of population-matched controls were used (controls with negative cancer history, and general population controls). Germline pathogenic variants (PV) in main predisposition genes were identified in 18 (8.0%) PDAC patients. The most mutated gene was BRCA2 (50% of carriers). PDAC risk was significantly elevated in carriers of PV in BRCA1 (OR = 10.4, p = 0.04), BRCA2 (OR = 6.4, p = 0.0009), and CHEK2 (OR = 17.5, p = 0.003). Germline mutations in genes participating in homologous recombination processes were associated with improved overall survival of patients. Among EC patients there were 60 (11.4%) carriers of PV in main predisposition genes. Carriers of PV in Lynch syndrome (LS) genes had markedly elevated risk of developing EC (OR = 22.4, p...
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Rare cells in diagnostics and monitoring of gynecological diseases
Kiss, Imrich ; Bobek, Vladimír (advisor) ; Špaček, Jiří (referee) ; Klézl, Petr (referee)
In the last two decades there is an enormous effort to discover a non-invasive marker to diagnose, predict and monitor therapy effect of malignant diseases. Circulating tumor cells (CTC) have the ability to fulfil all these criteria. The introduction of the monothematic thesis deals with the problematics of CTC in general and its application in clinical medicine. It is followed by the author's first publication, which reviews the current status of CTC in gynecological malignancies. The next publication is an original article about CTC in patients with endometrial carcinoma. It reports a successful isolation of vital CTC in 75% of tested patients and identifies CTC as an individual marker of the disease without correlation to the stage, grade or lymph nodes involvement. The second part of this thesis deals with endometriosis, a benign but often recurrent disease worsening the life quality of women in reproductive age. The multicentre study presents a successful isolation of circulating endometrial cells (CEC) in patients with histologically proven endometriosis with various stages and symptoms. From the total of 423 samples 78.4% were CEC positive. Eleven patients were monitored during their menstrual cycle and CEC tested in different phases, being the early post-ovulatory period in which the...
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The role of untrasound assessment of adverse prognostic factors for surgical procedure tailoring in endometrial cancer patients
Frühauf, Filip ; Fischerová, Daniela (advisor) ; Halaška, Michael (referee) ; Burgetová, Andrea (referee)
Objectives: Preoperative ultrasound including assessment of local extent of disease in uterus, adnexal involvement and pelvic spread is recommended staging examination in patients with endometrial cancer. It is routinely based on subjective assessment by experienced sonographists. The main aim of the study was to assess if the objective methods based on simple measurements and calculations have diagnostic performance comparable to that of subjective evaluation in detection of deep myometrial invasion. Two traditional objective techniques were tested - (1) deepest invasion / normal myometrium width ratio proposed by Gordon and (2) tumor / uterine anteroposterior diameter ratio introduced by Karlsson. Methods: The prospective diagnostic accuracy study was initiated at Gynecologic Oncology Centre. All consecutive patients with histologically verified endometrial cancer undergoing transvaginal or transrectal sonography using predefined study protocol followed by surgical staging procedure were prospectively enrolled . Local staging of each endometrial tumor was subjectively evaluated by one of experienced sonographists, myometrial invasion was assessed as deep (≥ 50 %) or superficial (˂ 50 %) and cervical stromal involvement as present or absent. Concurrently, the depth of myometrial invasion was...
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