BACKGROUND: The breast and ovarian cancer susceptibility gene BRCA1 encodes a multifunctional tumor suppressor protein BRCA1, which is involved in regulating cellular processes such as cell cycle, transcription, DNA repair, DNA damage response and chromatin remodeling. BRCA1 protein, located primarily in cell nuclei, interacts with multiple proteins and various DNA targets. It has been demonstrated that BRCA1 protein binds to damaged DNA and plays a role in the transcriptional regulation of downstream target genes. As a key protein in the repair of DNA double-strand breaks, the BRCA1-DNA binding properties, however, have not been reported in detail. RESULTS: In this study, we provided detailed analyses of BRCA1 protein (DNA-binding domain, amino acid residues 444-1057) binding to topologically constrained non-B DNA structures (e.g. cruciform, triplex and quadruplex). Using electrophoretic retardation assay, atomic force microscopy and DNA binding competition assay, we showed the greatest preference of the BRCA1 DNA-binding domain to cruciform structure, followed by DNA quadruplex, with the weakest affinity to double stranded B-DNA and single stranded DNA. While preference of the BRCA1 protein to cruciform structures has been reported previously, our observations demonstrated for the first time a preferential binding of the BRCA1 protein also to triplex and quadruplex DNAs, including its visualization by atomic force microscopy. CONCLUSIONS: Our discovery highlights a direct BRCA1 protein interaction with DNA. When compared to double stranded DNA, such a strong preference of the BRCA1 protein to cruciform and quadruplex structures suggests its importance in biology and may thus shed insight into the role of these interactions in cell regulation and maintenance.

• Klíčová slova
• BRCA1 protein, DNA binding, Protein-DNA complex,
• MeSH
• B-DNA chemie   metabolismus   MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• protein BRCA1 chemie   metabolismus   MeSH
• proteinové domény MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• B-DNA MeSH
• BRCA1 protein, human MeSH Prohlížeč
• protein BRCA1 MeSH

PURPOSE: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. METHODS: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. RESULTS: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. CONCLUSION: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.

• Klíčová slova
• BRCA1, BRCA2, Cancer risks, Missense variants,
• MeSH
• genetická predispozice k nemoci MeSH
• genetické testování metody   MeSH
• geny BRCA1 MeSH
• geny BRCA2 MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu * genetika   patologie   MeSH
• nádory vaječníků * genetika   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• BRCA1 protein, human MeSH Prohlížeč
• BRCA2 protein, human MeSH Prohlížeč
• protein BRCA1 MeSH
• protein BRCA2 MeSH

BRCA1 is a tumour suppressor gene with a caretaker function in the DNA-damage repair and the maintenance of genome integrity. The human BRCA1 and NBR2 genes and the homologous Brcal and Nbr1 mouse genes are situated head-to-head on human chromosome 17q21 and on mouse chromosome 11, respectively. Their transcription start sites, located on opposite DNA strands, are separated by 218 bp in humans, and by 289 bp in mice. Because of this intimate contact and because of our previous observation of a quasi-reciprocal expression pattern of Brca1 and Nbr1 in mouse spermatogenesis, we estimated here the relative mRNA expression of BRCA1, NBR1 (next-to-BRCA1) and NBR2 genes in a panel of permanent cell lines and primary cell cultures derived from human breast cancer or normal mammary tissue. The analysis revealed highly significant downregulation of BRCA1 in 11 out of 12 examined tumour cell lines and primary cell cultures as compared to non-malignant mammary cells. Two isoforms of NBR1(1A) and the classical NBR1(1B) transcripts were found in cells from malignant mammary tissues, all of them downregulated in respect to normal cells. The expression of NBR2 differed, being increased in three permanent tumour cell lines and slightly decreased in all primary breast cancer cell cultures. The in silico analysis revealed two new putative domains of the predicted NBR1 protein, suggesting its role in the ubiquitin pathway. The recent identification of the ubiquitin protein ligase activity of BRCA1 implies a possible functional connection between both genes.

• MeSH
• alternativní sestřih MeSH
• duktální karcinom prsu genetika   metabolismus   patologie   MeSH
• epitelové buňky metabolismus   MeSH
• geny BRCA1 * MeSH
• intracelulární signální peptidy a proteiny MeSH
• kultivované buňky MeSH
• lidé MeSH
• messenger RNA genetika   izolace a purifikace   MeSH
• nádorové buňky kultivované metabolismus   MeSH
• nádorové proteiny biosyntéza   genetika   MeSH
• nádory prsu genetika   metabolismus   patologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• protein - isoformy biosyntéza   genetika   MeSH
• protein BRCA1 biosyntéza   MeSH
• proteiny genetika   MeSH
• proteosyntéza * MeSH
• prsy cytologie   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• RNA dlouhá nekódující MeSH
• RNA nádorová genetika   izolace a purifikace   MeSH
• terciární struktura proteinů MeSH
• transkripční faktory * MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• intracelulární signální peptidy a proteiny MeSH
• messenger RNA MeSH
• nádorové proteiny MeSH
• NBR1 protein, human MeSH Prohlížeč
• Nbr1 protein, mouse MeSH Prohlížeč
• NBR2 lncRNA, human MeSH Prohlížeč
• protein - isoformy MeSH
• protein BRCA1 MeSH
• proteiny MeSH
• RNA dlouhá nekódující MeSH
• RNA nádorová MeSH
• transkripční faktory * MeSH

Mutations in the BRCA1 and BRCA2 tumour suppressor genes are associated with prostate cancer risk; however, optimal screening protocols for individuals with these mutations have been a subject of debate. Several prospective studies of prostate cancer incidence and screening among BRCA1/2 mutation carriers have indicated at least a twofold to fourfold increase in prostate cancer risk among carriers of BRCA2 mutations compared with the general population. Moreover, BRCA2 mutations are associated with more aggressive, high-grade disease characteristics at diagnosis, more aggressive clinical behaviour and greater prostate cancer-specific mortality. The risk for BRCA1 mutations seems to be attenuated compared with BRCA2. Prostate-specific antigen (PSA) measurement or prostate magnetic resonance imaging (MRI) alone is an imperfect indicator of clinically significant prostate cancer; therefore, BRCA1/2 mutation carriers might benefit from refined risk stratification strategies. However, the long-term impact of prostate cancer screening is unknown, and the optimal management of BRCA1/2 carriers with prostate cancer has not been defined. Whether timely localized therapy can improve overall survival in the screened population is uncertain. Long-term results of prospective studies are awaited to confirm the optimal screening strategies and benefits of prostate cancer screening among BRCA1/2 mutation carriers, and whether these approaches ultimately have a positive impact on survival and quality of life in these patients.

• MeSH
• časná detekce nádoru metody   MeSH
• genetická predispozice k nemoci MeSH
• geny BRCA1 MeSH
• kvalita života MeSH
• lidé MeSH
• mutace MeSH
• nádory prostaty * diagnóza   genetika   terapie   MeSH
• prospektivní studie MeSH
• prostatický specifický antigen genetika   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• zárodečné buňky patologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• BRCA1 protein, human MeSH Prohlížeč
• prostatický specifický antigen MeSH
• protein BRCA1 MeSH
• protein BRCA2 MeSH

BACKGROUND: BRCA1 codes for a tumor suppressor protein involved in DNA repair. Based on the role of single nucleotide polymorphisms (SNPs) in the modification of gene expression and function and the existence of certain SNPs within 3-untranslated region of BRCA1 with the ability to change binding sites for mirRNAs, several association studies have been designed to explore the significance of SNPs within BRCA1 gene in conferring breast cancer (BC) risk. This study aims to assess the relationship between BRCA1 SNPs and BC using meta-analysis. AIM: To conduct a meta-analysis for retrieving case-control studies on the associations between the rs11655505, rs1799966, rs3737559, rs1799950, rs799917 and rs16941 BRCA1 polymorphisms and BC. The pooled odds ratios and its 95% confidence intervals were measured using fixed and random model to define the association between these polymorphisms and BC risk. CONCLUSION: No significant association was found for any of these polymorphisms and BC risk in the allelic, homozygote, dominant or recessive models. Overall, our study implies that the mentioned polymorphisms are not associated with BC risk. However, our study did not exclude the possible contribution of other SNPs within this gene in BC nor substantial contribution of multiple variants within this gene in conferring BC risk. Key words: BRCA1 - breast cancer - meta-analysis.

• Klíčová slova
• BRCA1 - breast cancer - meta-analysis,
• MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• nádory prsu genetika   MeSH
• protein BRCA1 genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• BRCA1 protein, human MeSH Prohlížeč
• protein BRCA1 MeSH

Dysfunction of tumor suppressor genes BRCA1 and BRCA2 is involved in the pathogenesis of malignant tumors, especially breast and ovarian carcinoma. BRCA1/2 genes may be inactivated by germinal and somatic mutations or epigenetic changes. Germinal mutations are responsible for the hereditary breast and ovarian carcinoma syndrome. Defects of BRCA1/2 genes lead to the failure of homologous recombination, the basic mechanism for DNA double strand break repair. The resultant genomic instability is associated with a high risk of malignant transformation of the cell, but it also results in a higher sensitivity of tumors to platinum-based chemotherapeutic compounds which damage DNA structure directly. Inhibitors of poly(ADP-ribose) polymerase (PARP) are the next generation of antitumor agents aimed on the suppression of DNA single strand break repair. In homologous recombination deficient tumors, PARP inhibitors lead to accumulation of DNA damage and death of neoplastic cells through the mechanism of synthetic lethality. Platinum-based agents and PARP inhibitors are effective not only against tumors with germinal and somatic BRCA1/2 mutations but also against sporadic carcinomas with epigenetic BRCA1/2 inactivation or with defects of other independent genes involved in the control of homologous recombination. This phenomenon is represented by the term "BRCAness". Mutational analysis is used for the assessment of BRCA1/2 status, but it is complicated by the prominent length of BRCA1/2 genes and a wide spectrum of possible genetic alterations. Therefore, next generation sequencing seems to represent an optimal approach for BRCA1/2 evaluation nowadays. Development of reliable diagnostic tests for BRCAness in sporadic tumors and efforts to reverse platinum and PARP inhibitors resistance represent the key objectives of the forthcoming research.

• Klíčová slova
• BRCA1 - BRCA2 - hereditary breast and ovarian carcinoma - chemotherapy - PARP inhibitors - BRCAness.,
• MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• homologní rekombinace MeSH
• lidé MeSH
• mutace MeSH
• nádory prsu farmakoterapie   genetika   patologie   MeSH
• nádory vaječníků farmakoterapie   genetika   patologie   MeSH
• oprava DNA účinky léků   MeSH
• PARP inhibitory farmakologie   terapeutické užití   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• vysoce účinné nukleotidové sekvenování * MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• BRCA1 protein, human MeSH Prohlížeč
• BRCA2 protein, human MeSH Prohlížeč
• PARP inhibitory MeSH
• protein BRCA1 MeSH
• protein BRCA2 MeSH

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

• Klíčová slova
• BRCA1, BRCA2, breast cancer, ethnicity, geography, mutation, ovarian cancer,
• MeSH
• databáze genetické MeSH
• internacionalita * MeSH
• lidé MeSH
• mutace genetika   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• rodina MeSH
• zeměpis MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• BRCA1 protein, human MeSH Prohlížeč
• BRCA2 protein, human MeSH Prohlížeč
• protein BRCA1 MeSH
• protein BRCA2 MeSH

Development of targeted cancer therapy is accompanied by a search for markers allowing prediction of response to the particular treatment. Recently, the interest is focused, among other neoplasms, also on the therapy of ovarian cancer using new inhibitors of poly (ADP-ribose) polymerase (PARP) proteins, nuclear enzymes involved in the repair of single-stranded DNA breaks. The greatest benefit from the administration of PARP inhibitors have patients with a deleterious or potentially deleterious germ-line or somatic mutation of BRCA1 or BRCA2, two genes responsible for repair of double stranded DNA breaks. There has been described a wide spectrum of mutations of BRCA 1/2, from point substitutions to large deletions, including sometimes even several exons of the gene.Unlike the testing of germ-line mutations provided for many years by the medical geneticists, somatic mutations in the tumor tissue have not been routinely tested so far. Detection of BRCA1/2 mutations in the tumor is significantly different from testing of germ-line mutations. In comparison with the analysis of DNA isolated from blood samples, testing of DNA isolated from the FFPE tissue encounters challenges based on heterogeneous representation of tumor cells in the tissue samples, on the presence of multiple neoplastic clones and on the infiltration of tissue by the non-neoplastic elements, as well as difficulties caused by variable proportion of apoptotic and necrotic cells deteriorating the overall quality of isolated DNA.Regarding the testing methods, NGS appears to be the optimal choice because of its complexity, speed of implementation into routine diagnostics as well as sensitivity for detection of a BRCA 1/2 mutations. When introduced into everyday laboratory practice, the functioning quality control system is of utmost importance. Provided there is a high probability of detection of the so far unreported variations in BRCA 1/2 genes, an introduction of a shared database of somatic variants diagnosed in the Czech Republic would be of enormous benefit.

• Klíčová slova
• BRCA1 - BRCA2 - ovarian cancer - FFPE - DNA sequencing - next generation sequencing - NGS.,
• MeSH
• lidé MeSH
• mutační analýza DNA metody   MeSH
• nádory prsu genetika   patologie   MeSH
• nádory vaječníků genetika   patologie   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• zárodečné mutace * MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• BRCA1 protein, human MeSH Prohlížeč
• BRCA2 protein, human MeSH Prohlížeč
• protein BRCA1 MeSH
• protein BRCA2 MeSH

Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

• Klíčová slova
• BAP1, BRCA1, UPS, cancer, chromatin remodeling, deubiquitination, histone 2A, intellectual disability, neurodevelopment, tumor, ubiquitin, ubiquitin-proteasome system,
• MeSH
• chromatin chemie   imunologie   MeSH
• dítě MeSH
• faktor C1 hostitelské buňky genetika   imunologie   MeSH
• heterozygot MeSH
• histony genetika   imunologie   MeSH
• kojenec MeSH
• lidé MeSH
• missense mutace * MeSH
• mladiství MeSH
• mutace ztráty funkce * MeSH
• nádorové supresorové proteiny nedostatek   genetika   imunologie   MeSH
• neurovývojové poruchy genetika   imunologie   patologie   MeSH
• předškolní dítě MeSH
• proteasomový endopeptidasový komplex genetika   imunologie   MeSH
• protein BRCA1 genetika   imunologie   MeSH
• regulace genové exprese MeSH
• restrukturace chromatinu genetika   imunologie   MeSH
• rodina MeSH
• T-lymfocyty imunologie   patologie   MeSH
• thiolesterasa ubikvitinu nedostatek   genetika   imunologie   MeSH
• ubikvitin genetika   imunologie   MeSH
• ubikvitinace MeSH
• ubikvitinligasy genetika   imunologie   MeSH
• zárodečné mutace * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• BAP1 protein, human MeSH Prohlížeč
• BARD1 protein, human MeSH Prohlížeč
• BRCA1 protein, human MeSH Prohlížeč
• chromatin MeSH
• faktor C1 hostitelské buňky MeSH
• HCFC1 protein, human MeSH Prohlížeč
• histony MeSH
• nádorové supresorové proteiny MeSH
• proteasomový endopeptidasový komplex MeSH
• protein BRCA1 MeSH
• thiolesterasa ubikvitinu MeSH
• ubikvitin MeSH
• ubikvitinligasy MeSH

Hereditary breast cancer syndrome is associated with a higher risk of developing breast cancer and accounts for 5-10% of all breast tumors. Is it possible that mutations in BRCA1/2 genes (which are involved in DNA repair genes) should be treated differently from sporadic breast cancer? In addition to anthracyclines, taxanes are effective against tumors with a BRCA2 mutation. A TNT trial showed that platinum derivatives have marked effects against metastatic breast cancer. Data from neoadjuvant trials testing efficacy in triple negative cancer confirm that neoadjuvant chemotherapy is more effective against sporadic tumors, whereas the effect of carboplatin is not statistically significant, as opposed to sporadic cancer. A new group of therapeutics, particularly for tumors with mutations in BRCA1/2 genes, is PARP inhibitors. These treatments were effective not only against triple negative tumors but also against luminal tumors. The author declares she has no potential confllcts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 5. 6. 2019 Accepted: 12. 6. 2019.

• Klíčová slova
• BRCA1/2 mutation, PARP inhibitors, breast cancer, genomic tests, platinum salts,
• MeSH
• antitumorózní látky terapeutické užití   MeSH
• lidé MeSH
• mutace MeSH
• nádory prsu farmakoterapie   genetika   MeSH
• neoadjuvantní terapie MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH
• BRCA1 protein, human MeSH Prohlížeč
• BRCA2 protein, human MeSH Prohlížeč
• protein BRCA1 MeSH
• protein BRCA2 MeSH