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1. Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling (PubMed)

Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively (...) inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity. In cells, Bractoppin inhibits substrate recognition detected by Förster resonance energy transfer, and diminishes BRCA1 recruitment to DNA breaks, in turn suppressing damage-induced G2

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2018 Cell chemical biology

2. Risk-reducing bilateral salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations. (PubMed)

Risk-reducing bilateral salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations. The presence of deleterious mutations in breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2) significantly increases the risk of developing some cancers, such as breast and high-grade serous cancer (HGSC) of ovarian, tubal and peritoneal origin. Risk-reducing salpingo-oophorectomy (RRSO) is usually recommended to BRCA1 or BRCA2 carriers after completion of childbearing. Despite prior systematic (...) reviews and meta-analyses on the role of RRSO in reducing the mortality and incidence of breast, HGSC and other cancers, RRSO is still an area of debate and it is unclear whether RRSO differs in effectiveness by type of mutation carried.To assess the benefits and harms of RRSO in women with BRCA1 or BRCA2 mutations.We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 7) in The Cochrane Library, MEDLINE Ovid, Embase Ovid and trial registries, with no language

2018 Cochrane

3. Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer

Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer | JMG Contact blog by Pathogenic germline variants in BRCA1 and BRCA2 genes confer increased breast/ovarian cancer (BC/OC) risks (...) . The identification of deleterious BRCA1/2 genetic variants in BC/OC families guides the enrollment of carriers in medical surveillance and cancer prevention programs and informs treatment decisions by more precisely targeted cancer therapies. BRCA1/2 genetic analysis commonly includes only coding regions. However, no deleterious variant is identified in a significant fraction of families. We have studied the intronic regions of these genes to identify pathogenic variants that would be undetected during

2018 JMG Contact blog

4. BRCA1 founder mutations and beyond in the Polish population: A single-institution BRCA1/2 next-generation sequencing study. (PubMed)

BRCA1 founder mutations and beyond in the Polish population: A single-institution BRCA1/2 next-generation sequencing study. Hereditary mutations in BRCA1/2 genes increase the risk of breast cancer by 60-80% and ovarian cancer by about 20-40% in female carriers. Detection of inherited mutations in asymptomatic carriers allows for the implementation of appropriate preventive measures. BRCA1/2 genotyping is also important for poly(adenosine diphosphate)-ribose polymerase (PARP) inhibitor (...) administration. This work addresses the need for next-generation sequencing (NGS) technology for the detection of BRCA1/2 mutations in Poland where until recently mostly founder mutations have been tested, and whether BRCA diagnostics should be extended beyond the panel of founder mutations in this population. The study comprises 2931 patients who were referred for genetic counseling and tested for founder and recurrent mutations in BRCA1 (5382insC (c.5266dupC; p.Gln1756Profs), c.5370C>T (c.5251C>T; p.R1751

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2018 PLoS ONE

5. Practice Advisory: Response to FDA?s Authorization of BRCA1 and BRCA2 Gene Mutation Direct-to-Consumer Testing

Practice Advisory: Response to FDA?s Authorization of BRCA1 and BRCA2 Gene Mutation Direct-to-Consumer Testing Practice Advisory: Response to FDA’s Authorization of BRCA1 and BRCA2 Gene Mutation Direct-to-Consumer Testing - ACOG Menu ▼ Practice Advisory: Response to FDA’s Authorization of BRCA1 and BRCA2 Gene Mutation Direct-to-Consumer Testing Page Navigation ▼ Share: Practice Advisory: Response to FDA’s Authorization of BRCA1 and BRCA2 Gene Mutation Direct-to-Consumer Testing This Practice (...) Advisory has been endorsed by the American College of Medical Genetics and Genomics, National Society of Genetic Counselors, Nurse Practitioners in Women’s Health, and the Society for Gynecologic Oncology. On 6 March 2018, The U. S. Food and Drug Administration (FDA) authorized the 23andMe, Inc., Personal Genome Service ® Genetic Health Risk Report for BRCA1 and BRCA2 (Selected Variants) (1). This is the first direct-to-consumer test to report on BRCA1 and BRCA2 gene mutations. The test evaluates three

2018 Society of Gynecologic Oncology

6. Screening of <i>BRCA1/2</i> deep intronic regions by targeted gene sequencing identifies the first germline <i>BRCA1</i> variant causing pseudoexon activation in a patient with breast/ovarian cancer. (PubMed)

Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer. Genetic analysis of BRCA1 and BRCA2 for the diagnosis of hereditary breast and ovarian cancer (HBOC) is commonly restricted to coding regions and exon-intron boundaries. Although germline pathogenic variants in these regions explain about ~20% of HBOC cases, there is still an important fraction (...) that remains undiagnosed. We have screened BRCA1/2 deep intronic regions to identify potential spliceogenic variants that could explain part of the missing HBOC susceptibility.We analysed BRCA1/2 deep intronic regions by targeted gene sequencing in 192 high-risk HBOC families testing negative for BRCA1/2 during conventional analysis. Rare variants (MAF <0.005) predicted to create/activate splice sites were selected for further characterisation in patient RNA. The splicing outcome was analysed by RT-PCR

2018 Journal of Medical Genetics

7. Cyclin B1 stability is increased by interaction with BRCA1, and its overexpression suppresses the progression of BRCA1-associated mammary tumors (PubMed)

Cyclin B1 stability is increased by interaction with BRCA1, and its overexpression suppresses the progression of BRCA1-associated mammary tumors Germline BRCA1 mutations predispose women to breast and ovarian cancer. BRCA1, a large protein with multiple functional domains, interacts with numerous proteins involved in many important biological processes and pathways. However, to date, the role of BRCA1 interactions at specific stages in the progression of mammary tumors, particularly in relation (...) to cell cycle regulation, remains elusive. Here, we demonstrate that BRCA1 interacts with cyclin B1, a crucial cell cycle regulator, and that their interaction is modulated by DNA damage and cell cycle phase. In DNA-damaged mitotic cells, BRCA1 inhibits cytoplasmic transportation of cyclin B1, which prevents cyclin B1 degradation. Moreover, restoration of cyclin B1 in BRCA1-deficient cells reduced cell survival in association with induction of apoptosis. We further demonstrate that treatment of Brca1

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2018 Experimental & molecular medicine

8. LYNPARZA (olaparib), PARP inhibitor - BRCA1- or BRCA2-mutated high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer

LYNPARZA (olaparib), PARP inhibitor - BRCA1- or BRCA2-mutated high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer LYNPARZA SUMMARY CT14098

2016 Haute Autorite de sante

9. A novel BRCA1-associated protein-1 isoform affects response of mesothelioma cells to drugs impairing BRCA1-mediated DNA repair. (PubMed)

A novel BRCA1-associated protein-1 isoform affects response of mesothelioma cells to drugs impairing BRCA1-mediated DNA repair. BRCA1 associated protein1 (BAP1) is a tumor suppressor involved in multiple cellular processes such as transcriptional regulation, chromatin modification by deubiquitinating histone 2A, and DNA repair. BAP1 mutations are frequent in malignant pleural mesothelioma (MPM). Our aim was to functionally characterize a newly identified isoform of BAP1 and investigate (...) ) cytotoxicity, and this sensitivity is enhanced when olaparib treatment is combined with GDC0980 (a dual PI3K-mTOR inhibitor), which induces downregulation of BRCA1.These observations suggest that BAP1Δ does regulate DNA damage response and influences drug sensitivity. It might therefore be relevant to investigate whether patients with high expression of BAP1Δ may be responsive to PARP/PI3K-mTOR inhibitors.Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc

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2017 Journal of Thoracic Oncology

10. Transcriptional signature of lymphoblastoid cell lines of BRCA1, BRCA2 and non-BRCA1/2 high risk breast cancer families (PubMed)

Transcriptional signature of lymphoblastoid cell lines of BRCA1, BRCA2 and non-BRCA1/2 high risk breast cancer families Approximately 25% of hereditary breast cancer cases are associated with a strong familial history which can be explained by mutations in BRCA1 or BRCA2 and other lower penetrance genes. The remaining high-risk families could be classified as BRCAX (non-BRCA1/2) families. Gene expression involving alternative splicing represents a well-known mechanism regulating the expression (...) of multiple transcripts, which could be involved in cancer development. Thus using RNA-seq methodology, the analysis of transcriptome was undertaken to potentially reveal transcripts implicated in breast cancer susceptibility and development. RNA was extracted from immortalized lymphoblastoid cell lines of 117 women (affected and unaffected) coming from BRCA1, BRCA2 and BRCAX families. Anova analysis revealed a total of 95 transcripts corresponding to 85 different genes differentially expressed

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2017 Oncotarget

11. Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls (PubMed)

Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls Comparison of variant frequencies in the general population has become an essential part of the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for interpreting sequence variants. We determined the optimal number of relevant ethnic controls that should be used (...) to accurately calculate the odds ratio (OR) of genetic variants.Using the ACMG guidelines, we reclassified BRCA1 and BRCA2 mutations and variants of unknown significance in 745 Korean patients susceptible to hereditary breast and ovarian cancer compared with 1,314 Korean population controls.We observed that the ORs were falsely inflated when we analyzed several variants using non-Korean population data. Our simulation indicated that the number of controls needed for the lower limit of a 95% confidence

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2017 Cancer research and treatment : official journal of Korean Cancer Association

12. BRCA1 regulation on β-hCG: a mechanism for tumorigenicity in BRCA1 defective breast cancer (PubMed)

BRCA1 regulation on β-hCG: a mechanism for tumorigenicity in BRCA1 defective breast cancer Human chorionic gonadotropin β (β-hCG) has been implicated in breast tumorigenesis. However, the role of this hormone is highly controversial as certain studies suggest it has anti-tumor properties while others have found it to be pro-tumorigenic. To unveil the truth, we have analyzed the expression of β-hCG in breast cancer. We identified for the first time that β-hCG expression is linked to BRCA1 (...) status and its overexpression is seen in BRCA1 mutated breast cancer cells, BRCA1 conditional knockout mouse breast cancer tissues and BRCA1 floxed basal cell carcinoma (BCC) tissues. An analysis of three large, transcriptomic data sets from TCGA (The Cancer Genome Atlas) expression profile confirmed the inverse correlation between BRCA1 and β-hCG in human breast cancer. Using ChIP and luciferase assays, we also demonstrated that the cancer cells with wild-type but not mutant BRCA1 directly repress

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2017 Oncogenesis

13. The PARP-1 inhibitor Olaparib suppresses BRCA1 protein levels, increases apoptosis and causes radiation hypersensitivity in BRCA1+/- lymphoblastoid cells (PubMed)

The PARP-1 inhibitor Olaparib suppresses BRCA1 protein levels, increases apoptosis and causes radiation hypersensitivity in BRCA1+/- lymphoblastoid cells The use of polyADPribose polymerase inhibitors in cancer treatment provides a unique opportunity to target DNA repair processes in cancer cells while leaving normal tissue intact. The PARP-1 enzyme repairs DNA single strand breaks (SSB). Therefore PARP-1 inhibition in BRCA1 negative cancers results in the formation of cytotoxic DNA double (...) strand breaks (DSB) causing synthetic lethality. The use of PARP1 inhibitors is gaining momentum in the treatment of a variety of tumours with BRCA1 involvement including breast, ovarian, pancreatic and prostate cancer. Our previous work showed that the PARP-1 inhibitor Olaparib causes both hypersensitivity of BRCA1+/- cells following exposure to gamma radiation due to the persistence of DNA strand breaks in cells, measured by the DNA damage biomarker γ-H2AX. Therefore dual treatment of cancers

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2017 Journal of Cancer

14. Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer (PubMed)

Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer The current rearrangement ratio of BRCA1 and BRCA2 genes is not known in the Turkish population. Rearrangements are not routinely investigated in many Turkish laboratories. This creates problems and contradictions between clinics. Therefore, the aim of this study was to evaluate the distribution and frequency of rearrangements in BRCA1 and BRCA2 genes (...) in high-risk families and to clarify the limits of BRCA1 and BRCA2 testing in Turkey.The study included 1809 patients at high risk of breast cancer or ovarian cancer. All patients were investigated for both small indels and rearrangements of BRCA genes using DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis.The overall frequency of rearrangements was 2% (25/1262). The frequency of rearrangements was 1.7% (18/1086) and 4% (9/206) in patients with breast cancer

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2018 European journal of breast health

15. Prevalence of BRCA1 and BRCA2 Mutations Among High-Risk Saudi Patients With Breast Cancer (PubMed)

Prevalence of BRCA1 and BRCA2 Mutations Among High-Risk Saudi Patients With Breast Cancer Purpose Over the past three decades, the incidence rate of breast cancer (BC) among Arab women has continually increased. However, data on the prevalence of BRCA1/2 mutations are scarce. Although the population in Saudi Arabia is at large homogeneous and consanguinity is common, especially in the central, eastern, and southern regions of the country, the prevalence of BRCA1 and BRCA2 mutations (...) and the characteristics of BC are not well studied in the country. Methods This prospective observational study intended to determine the prevalence of BRCA1 and BRCA2 mutations and sought to examine the clinicopathologic features of BC associated with these mutations. Results Of 310 patients, 270 (87%) had no mutation. BRCA mutations were identified in 40 patients; BRCA1 mutations were found in 11% of patients, and BRCA2 mutations were found in 2% of patients. Variants of unknown significance were found in 15

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2018 Journal of global oncology

16. Clinical testing of BRCA1 and BRCA2: a worldwide snapshot of technological practices (PubMed)

Clinical testing of BRCA1 and BRCA2: a worldwide snapshot of technological practices Clinical testing of BRCA1 and BRCA2 began over 20 years ago. With the expiration and overturning of the BRCA patents, limitations on which laboratories could offer commercial testing were lifted. These legal changes occurred approximately the same time as the widespread adoption of massively parallel sequencing (MPS) technologies. Little is known about how these changes impacted laboratory practices (...) for detecting genetic alterations in hereditary breast and ovarian cancer genes. Therefore, we sought to examine current laboratory genetic testing practices for BRCA1/BRCA2. We employed an online survey of 65 questions covering four areas: laboratory characteristics, details on technological methods, variant classification, and client-support information. Eight United States (US) laboratories and 78 non-US laboratories completed the survey. Most laboratories (93%; 80/86) used MPS platforms to identify

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2018 NPJ genomic medicine

17. Association of BRCA1- and BRCA2-deficiency with mutation burden, expression of PD-L1/PD-1, immune infiltrates, and T cell-inflamed signature in breast cancer. (PubMed)

Association of BRCA1- and BRCA2-deficiency with mutation burden, expression of PD-L1/PD-1, immune infiltrates, and T cell-inflamed signature in breast cancer. Immune checkpoint inhibitors have demonstrated effective anti-tumour response in cancer types with high mutation burden (e.g. melanoma) and in subset of cancers with features of genomic instability (e.g. mismatch-repair deficiency). One possible explanation for this effect is the increased expression of immune checkpoint molecules and pre (...) -existing adaptive immune response in these cancers. Given that BRCA1 and BRCA2 are integral in maintaining genomic integrity, we hypothesise that the inactivation of these genes may give rise to breast cancers with such immunogenic phenotype. Therefore, using two large series of publicly available breast cancer datasets, namely that from The Cancer Genome Atlas and Wellcome Trust Institute, we sought to investigate the association between BRCA1- and BRCA2-deficiency with features of genomic instability

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2019 PLoS ONE

18. White Blood Cell BRCA1 Promoter Methylation Status and Ovarian Cancer Risk. (PubMed)

White Blood Cell BRCA1 Promoter Methylation Status and Ovarian Cancer Risk. The role of normal tissue gene promoter methylation in cancer risk is poorly understood.To assess associations between normal tissue BRCA1 methylation and ovarian cancer risk.2 case-control (initial and validation) studies.2 hospitals in Norway (patients) and a population-based study (control participants).934 patients and 1698 control participants in the initial study; 607 patients and 1984 control participants (...) in the validation study.All patients had their blood sampled before chemotherapy. White blood cell (WBC) BRCA1 promoter methylation was determined by using methylation-specific quantitative polymerase chain reaction, and the percentage of methylation-positive samples was compared between population control participants and patients with ovarian cancer, including the subgroup with high-grade serous ovarian cancer (HGSOC).In the initial study, BRCA1 methylation was more frequent in patients with ovarian cancer

2018 Annals of Internal Medicine

19. Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised tria

Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised tria In the phase 3 SOLO2 trial (ENGOT Ov-21), maintenance therapy with olaparib tablets significantly prolonged progression-free survival (primary endpoint) compared with placebo in patients with a germline BRCA1 or BRCA2 (BRCA1/2) mutation

2018 EvidenceUpdates

20. Identification of BRCA1 Deficiency Using Multi-Analyte Estimation of BRCA1 and Its Repressors in FFPE Tumor Samples from Patients with Triple Negative Breast Cancer (PubMed)

Identification of BRCA1 Deficiency Using Multi-Analyte Estimation of BRCA1 and Its Repressors in FFPE Tumor Samples from Patients with Triple Negative Breast Cancer Apart from germ-line BRCA1-mutated breast cancers, a significant proportion of women with sporadic triple negative breast cancer (TNBC) sub-type are known to harbour varying levels of BRCA1-dysfuction. There is currently no established diagnostic method to identify these patients.The analysis was performed on 183 primary breast (...) cancer tumor specimens from our longitudinal case-series archived as formalin-fixed-paraffin-embedded (FFPE) blocks comprising 71 TNBCs and 112 Hormone receptor positive HER2 negative (HR+HER2-) tumors. Transcript levels of BRCA1 and two of its repressors ID4 and microRNA182 were determined by TaqMan quantitative PCR. BRCA1 protein was detected immunohistochemically with the MS110 antibody.The representation of BRCA1 and its repressor ID4 as a ratio led to improved separation of TNBCs from HR+HER2

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2016 PloS one

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