A5006829875- BRCA gene mutations in cancer
- DNA Repair Mechanisms
- Nutrition, Genetics, and Disease
- Genetic factors in colorectal cancer
- Cancer Genomics and Diagnostics
- Genomic variations and chromosomal abnormalities
- Pancreatic and Hepatic Oncology Research
- CRISPR and Genetic Engineering
- Molecular Biology Techniques and Applications
- Cancer-related Molecular Pathways
- RNA Research and Splicing
- Genomics and Rare Diseases
- Ovarian cancer diagnosis and treatment
- Colorectal Cancer Treatments and Studies
- RNA modifications and cancer
- Genetics, Bioinformatics, and Biomedical Research
- RNA and protein synthesis mechanisms
- PARP inhibition in cancer therapy
- Cancer Treatment and Pharmacology
- Genetic Associations and Epidemiology
- Genomics and Chromatin Dynamics
- Breast Cancer Treatment Studies
- Biochemical and Molecular Research
- Animal Genetics and Reproduction
- Epigenetics and DNA Methylation
Charles University
2015-2024
General University Hospital in Prague
2013-2024
Czech Academy of Sciences, Institute of Molecular Genetics
2023
National Cancer Centre Singapore
2023
Czech Academy of Sciences
2005-2023
Research Institute of Inorganic Chemistry
2019
The Christie NHS Foundation Trust
2014
Centre for Human Genetics
2014
University of Oxford
2014
Center for Research in Molecular Medicine and Chronic Diseases
2012
PURPOSE To estimate age-specific relative and absolute cancer risks of breast to ovarian, pancreatic, male breast, prostate, colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these have not been extensively characterized. METHODS We analyzed data from 524 families PVs 21 countries. Complex segregation analysis was used (RRs; country-specific population incidences) cancers. The models allowed for residual familial aggregation ovarian were adjusted the...
The DNA damage response (DDR) pathway and its core component tumor suppressor p53 block cell cycle progression after genotoxic stress represent an intrinsic barrier preventing cancer development. serine/threonine phosphatase PPM1D/Wip1 inactivates promotes termination of the DDR pathway. Wip1 has been suggested to act as oncogene in a subset tumors that retain wild-type p53. In this paper, we have identified novel gain-of-function mutations exon 6 PPM1D result expression C-terminally...
Germline mutations in checkpoint kinase 2 ( CHEK2 ), a multiple cancer‐predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially published studies. We analyzed germline variants 1,928 high‐risk Czech breast/ovarian (BC/OC) patients and 3,360 population‐matched controls (PMCs). For functional classification of VUS, we developed complementation assay human nontransformed RPE1‐ ‐knockout cells quantifying CHK2‐specific phosphorylation endogenous protein...
Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and frequent association breast (BC). Genetic testing facilitates treatment preventive strategies reducing OC mortality in mutation carriers. However, prevalence germline mutations varies among populations many rarely mutated predisposition genes remain to be identified. We aimed analyze 219 1333 Czech patients 2278 population-matched controls using next-generation sequencing....
Abstract RAD18 is an E3 ubiquitin ligase that prevents replication fork collapse by promoting DNA translesion synthesis and template switching. Besides this classical role, has been implicated in homologous recombination; however, function incompletely understood. Here, we show recruited to lesions monoubiquitination of histone H2A at K15 counteracts accumulation 53BP1. Super-resolution microscopy revealed localizes the proximity double strand breaks limits distribution 53BP1 peripheral...
Alterations in dihydropyrimidine dehydrogenase gene (DPYD) coding for the key enzyme (DPD) of fluoropyrimidines (FPs) catabolism contribute to development serious FPs-related toxicity. We performed mutation analysis DPYD based on cDNA sequencing 76 predominantly colorectal cancer patients treated by FPs with early high (grade 3-4) hematological and/or gastrointestinal Six previously described [85T>C (C29R), 496A>G (M166V), 775A>G (K259E), 1601G>A (S534N), 1627A>G (I543V), IVS14+1G>A, 2194G>A...
Several reports indicate that inherited mutations in the PALB2 gene predispose to breast cancer. However, there is little agreement about clinical relevance and usefulness of mutation screening this gene. We analyzed prevalence spectrum germline estimate their contribution hereditary and/or ovarian cancer Czech Republic.The entire coding region was sequenced 409 breast/ovarian patients negative for BRCA1 BRCA2 mutations. Testing large genomic rearrangements (LGR) performed by multiplex...
Genetic testing for cancer predisposition leads to the identification of a number variants with uncertain significance. To some extent, BRCA1/2 have been classified, in contrast other genes. CHEK2 is typical example, which large unknown clinical significance were identified and still remained unclassified. Herein, variant assessment was performed through an vivo, yeast-based, functional assay. In total, 120 germline missense variants, distributed along protein sequence, two in-frame...
Abstract The most common histological subtypes of cutaneous melanoma include superficial spreading and nodular melanoma. However, the spectrum somatic mutations developed in those lesions all potential druggable targets have not yet been fully elucidated. We present results a sequence capture NGS analysis 114 primary melanomas identifying driver using biostatistical, immunohistochemical and/or functional approach. frequency pathogenic or likely variants were identified across 54 evaluated...
Germline DNA testing using the next-gene-ration sequencing (NGS) technology has become analytical standard for diagnostics of hereditary diseases, including cancer. Its increasing use places high demands on correct sample identification, independent confirmation prioritized variants, and their functional clinical interpretation. To streamline these processes, we introduced parallel RNA capture-based NGS identical capture panel CZECANCA, which is routinely used analysis cancer predisposition....
Germline mutations in the BRCA1 and BRCA2 genes have been shown to account for majority of hereditary breast ovarian cancers. The purpose our study was estimate incidence spectrum pathogenic BRCA1/2 high-risk Czech families. A total 96 families with recurrent and/or cancer 55 patients considered be at but no reported family history were screened genes. entire coding sequence each gene analyzed using a combination protein truncation test direct DNA sequencing. 35 identified (36.5%)....
The checkpoint kinase 2 gene (CHEK2) codes for the CHK2 protein, an important mediator of DNA damage response pathway. CHEK2 has been recognized as a multi-cancer susceptibility gene; however, its role in non-Hodgkin lymphoma (NHL) remains unclear. We performed mutation analysis entire coding sequence 340 NHL patients using denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA). Identified hereditary variants were genotyped 445...
Hereditary breast cancer comprises a minor but clinically meaningful ( BC ) subgroup. Mutations in the major ‐susceptibility genes are important prognostic and predictive markers; however, their carriers represent only 25% of high‐risk patients. To further characterize variants influencing risk, we performed SOLiD sequencing 581 325 patients (negatively tested previous BRCA1 / BRCA2 PALB2 analyses). In 105 (32%) patients, identified confirmed 127 truncating (89 unique; nonsense, frameshift...
Background Carriers of mutations in hereditary cancer predisposition genes represent a small but clinically important subgroup oncology patients. The identification causal germline determines follow-up management, treatment options and genetic counselling patients' families. Targeted next-generation sequencing-based analyses using cancer-specific panels high-risk individuals have been rapidly adopted by diagnostic laboratories. While the use diagnosis-specific is straightforward typical...
Breast cancer (BC) prognosis in BRCA1 and BRCA2 mutation carriers has been reported contradictorily, the significance of variables influencing sporadic BC is not established patients with hereditary BRCA1/BRCA2 mutations. In this retrospective cohort study, we analyzed effect clinicopathological characteristics on (disease-free survival [DFS] disease-specific [DSS]) carriers. We enrolled 234 899 non-carriers, whom 191 680 complete data, were available for analyses. found that ER-positive...
Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed splice acceptor shift in RNA analysis, introducing premature stop codon (p.Tyr337PhefsTer37). The was found 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and 4/3639 (0.11%) from independent German dataset. In addition, this 5/2966 (0.17%) (but none the 443 German) ovarian...
Abstract The subset of ovarian cancer (OC) diagnosed ≤ 30yo represents a distinct subgroup exhibiting disparities from late-onset OC in many aspects, including indefinite germline predisposition. We performed DNA/RNA-WES with HLA-typing, PRS assessment and survival analysis 123 early-onset OC-patients compared to histology/stage-matched unselected OC-patients, population-matched controls. Only 6/123(4.9%) carried pathogenic variant (GPV) high-penetrance OC-predisposition genes. Nevertheless,...