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Analysis of hereditary genetic variants predisposing to the development of familial forms of ovarian cancer.
Lhotová, Klára ; Soukupová, Jana (advisor) ; Mohelníková Duchoňová, Beatrice (referee) ; Weinberger, Vít (referee)
Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates preventive management for carriers of mutations in OC-susceptibility genes. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We analyzed 219 genes in 1333 Czech OC patients and 2278 population-matched controls (PMC) using next-generation sequencing. Altogether, 427/1333 (32%) patients and 58 /2278 (2,5%) PMC carried pathogenic mutations in 18 known/anticipated OC predisposition genes. Mutations in BRCA1, BRCA2, RAD51C, RAD51D, BARD1 and mismatch repair genes conferred a high OC risk (with OR>5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR ≥2 - <5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Results of this study demonstrate the high proportion...
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Analysis of cancer predisposition and functional analysis of variants of unknown significance
Stolařová, Lenka ; Kleibl, Zdeněk (advisor) ; Eckschlager, Tomáš (referee) ; Souček, Pavel (referee)
On average, 5-10% of all cancers occur in patients with hereditary tumors, who may have mutations in tens to hundreds of tumor predisposition genes. The phenotypes in mutation carriers overlap, and parallel analyses with sequencing panels is the method of choice in diagnostics. In our laboratory, we designed a universal panel and a targeted panel for a specific cancer, which allowed us to identify genetic alterations in patients with ovarian cancer, breast cancer, melanoma, and other cancers in the Czech Republic. The results of next generation sequencing (NGS) analyses show that the most frequent genetic alteration in ovarian cancers patients in the Czech Republic are hereditary mutations in BRCA1 (in 24% of unselected patients) and in malignant melanoma patients CDKN2A (in 2% of high risk patients). The presence of hereditary alterations is a clinically significant phenomenon affecting the prognosis and treatment of the disease. However, the interpretation of NGS findings is complicated by the presence of variants of unknown significance (VUS). We participate in the interpretation of VUS in the main predisposing genes BRCA1 and BRCA2 within the international consortium ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles). Our and international results of the most...
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Analysis of hereditary genetic variants predisposing to the development of familial forms of ovarian cancer.
Lhotová, Klára ; Soukupová, Jana (advisor) ; Mohelníková Duchoňová, Beatrice (referee) ; Weinberger, Vít (referee)
Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates preventive management for carriers of mutations in OC-susceptibility genes. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We analyzed 219 genes in 1333 Czech OC patients and 2278 population-matched controls (PMC) using next-generation sequencing. Altogether, 427/1333 (32%) patients and 58 /2278 (2,5%) PMC carried pathogenic mutations in 18 known/anticipated OC predisposition genes. Mutations in BRCA1, BRCA2, RAD51C, RAD51D, BARD1 and mismatch repair genes conferred a high OC risk (with OR>5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR ≥2 - <5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Results of this study demonstrate the high proportion...
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Intracellular signalling of Chk2 kinase and impact of its defects in oncogenesis
Stolařová, Lenka ; Kleibl, Zdeněk (advisor) ; Brábek, Jan (referee)
Chk2 (checkpoint kinase 2), a regulatory protein of the cell cycle checkpoints, is coded by CHEK2 gene. Chk2 belongs to serine/threonine kinase family and its dominant activity is in regulation and signal distribution of intracellular response to DNA damage. The upstream regulator of Chk2 protein is the ATM kinase that activates Chk2 by its phosphorylation on Thr68 localized in FHA domain. This in turn leads to the conformation change inducing homodimerization of Chk2 protomers and their activating phosphorylation within their kinase domains. Upon phosphorylation, catalytically active Chk2 protomers dissociate and phosphorylate various intracellular proteins (incl. p53, E2F-1, BRCA1, Cdc25A a C, BRCA2 a PLK3). By regulation of these proteins, Chk2 contributes to the cell cycle arrest, regulation of DNA repair and apoptosis. Germline mutations in CHEK2 gene were identified with the increased frequency in many human cancers, including breast and colorectal cancer. Hence, the failure of Chk2 intracellular activity contributes to the process of malignant transformation.
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