更新于：2024-11-01

BRCA2

更新于：2024-11-01

基本信息

别名

BRCA2、BRCA2 DNA repair associated、BRCC2

+ [8]

简介

Involved in double-strand break repair and/or homologous recombination. Binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). Acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. Part of a PALB2-scaffolded HR complex containing RAD51C and which is thought to play a role in DNA repair by HR. May participate in S phase checkpoint activation. Binds selectively to ssDNA, and to ssDNA in tailed duplexes and replication fork structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with PALB2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity. In concert with NPM1, regulates centrosome duplication. Interacts with the TREX-2 complex (transcription and export complex 2) subunits PCID2 and SEM1, and is required to prevent R-loop-associated DNA damage and thus transcription-associated genomic instability. Silencing of BRCA2 promotes R-loop accumulation at actively transcribed genes in replicating and non-replicating cells, suggesting that BRCA2 mediates the control of R-loop associated genomic instability, independently of its known role in homologous recombination (PubMed:24896180).

关联

项与 BRCA2 相关的药物

CAM833

靶点

BRCA2 x RAD51

作用机制

BRCA2 inhibitors [+1]

在研机构

University of Cambridge

原研机构

University of Cambridge

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

ARN-24922

靶点

BRCA2 x RAD51

作用机制

BRCA2 inhibitors [+1]

在研机构

Alma Mater Studiorum - Università di Bologna

原研机构

Alma Mater Studiorum - Università di Bologna

在研适应症

胰腺癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

ARN-24089

靶点

BRCA2 x RAD51

作用机制

BRCA2 inhibitors [+1]

在研机构

Alma Mater Studiorum - Università di Bologna

原研机构

Alma Mater Studiorum - Università di Bologna

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 BRCA2 相关的临床结果

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100 项与 BRCA2 相关的转化医学

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0 项与 BRCA2 相关的专利（医药）

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11,118

项与 BRCA2 相关的文献（医药）

2024-12-11·Journal of Biomolecular Structure and Dynamics

An in-silico investigation and network pharmacology based approach to explore the anti-breast-cancer potential of Tecteria coadunata (Wall.) C. Chr.

Article

作者: Baheti, Akshay M. ; Nagar, Shuchi ; Tagalpallewar, Amol A. ; More-Adate, Pallavi ; Pawar, Anil T. ; Ram, Shraddha

Uncontrolled cell proliferation is a common definition of cancer. After lung carcinoma, breast neoplasm is the second-most prevalent kind of cancer. The majority of breast cancer cells and healthy breast cells both have receptors for circulating oestrogen and progesterone. In order to promote the development and division of cancer cells, oestrogen and progesterone bind to the receptors and may collaborate with growth factors (such as oncogenes and mutant tumour suppressor genes). As per the literature, Tecteria coadunata (Wall.) C. Chr. has anticancer, antioxidant and anti-inflammatory potential. After the hydroalcoholic extraction of this rhizome, total of 200 phytochemicals were retrieved from HR-LCMS analysis. In this current study, Network pharmacology was carried out to explore the rationale of Tecteria coadunata (Wall.) C. Chr. by using different database using Cytoscape software. The network depicted the interaction of Bioactives with their targets and their association with several disease, especially breast cancer. Tecteria coadunata (Wall.) C. Chr. has offered new relationship with variety of genes and its applications in different types of breast cancers. Further Gene Ontology was carried out and it showed key targets were TP53, BRCA2, PGR and CHEK 2. Further Signalling pathways were also enriched. Flex-X software was used for molecular docking studies, and it verified that Dopaxanthin, Dantrolene and Orotidin shows the highest binding affinities with key targets. Additionally, Pharmacokinetic analysis revealed that all top three lead compounds which follows the Lipinski Rule (Rule of three) without interrupting the conditions of bioavailability with minimal toxicity.Communicated by Ramaswamy H. Sarma.

2024-12-01·Hormones

The molecular genetics of adrenal cushing

Review

作者: Vaduva, Patricia ; Bertherat, Jerome

Adrenal Cushing represents 20% of cases of endogenous hypercorticism. Unilateral cortisol-producing adenoma (CPA), a benign tumor, and adrenocortical carcinoma (ACC), a malignant tumor, are more frequent than bilateral adrenal nodular diseases (primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary pigmented nodular adrenal disease (PPNAD)).In cortisol-producing adrenal tumors, the signaling pathways mainly altered are the protein kinase A and Wnt/β-catenin pathways. Studying components of these pathways and exploring syndromic and familial cases of these tumors has historically enabled identification of many of the predisposing genes. More recently, pangenomic sequencing revealed alterations in sporadic tumors.In ACC, mainly due to TP53 alterations causing Li-Fraumeni syndrome, germline predisposition is frequent in children, while it is rare in adults. Pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2, which cause Lynch syndrome or alterations of IGF2 and CDKN1C (11p15 locus) in Beckwith-Wiedemann syndrome, can also cause ACC. Rarely, ACC is described in other hereditary tumor syndromes due to germline pathogenic variants in MEN1 or APC and, in very rare cases, NF1, SDH, PRKAR1A, or BRCA2. Concerning ACC somatic alterations, TP53 and genetic or epigenetic alterations at the 11p15 locus are also frequently described, as well as CTNNB1 and ZNRF3 pathogenic variants.CPAs mainly harbor somatic pathogenic variants in PRKACA and CTNNB1 and, less frequently, PRKAR1A, PRKACB, or GNAS1 pathogenic variants. Isolated PBMAH is due to ARMC5 inactivating pathogenic variants in 20 to 25% of cases and to KDM1A pathogenic variants in food-dependent Cushing. Syndromic PBMAH may be due to germline pathogenic variants in MEN1, APC, or FH, causing type 1 multiple endocrine neoplasia, familial adenomatous polyposis, or hereditary leiomyomatosis-kidney cancer syndrome, respectively. PRKAR1A germline pathogenic variants are the main alteration causing PPNAD (isolated or part of Carney complex).

2024-12-01·Breast Cancer Research and Treatment

Phenotypes of carriers of two mutated alleles in major cancer susceptibility genes

Article

作者: Koskinen, Lotta ; Friedman, Eitan ; Rabina, Daniel ; Laitman, Yael ; Bernstein-Molho, Rinal ; Niskakoski, Anni ; Koskenvuo, Juha

AbstractPurposeWhile cancer phenotypes in carriers of a single mutant allele in most major cancer susceptibility genes are well-established, there is a paucity of data on the phenotype of carriers of two pathogenic variants—double heterozygotes (DH) or homozygous carriers. Here, we describe the phenotype of carriers of homozygous and DH pathogenic sequence variants (PSVs) in major cancer susceptibility genes.MethodsIndividuals referred for multigene panel testing at Blueprint Genetics laboratory were included. Ethically approved comparison of cancer type and age at diagnosis between DH, homozygous, and single PSV carriers was performed per gene.ResultsOf 6,685 eligible participants, 928 (13.9%) were single heterozygous PSV carriers, 6 (0.09%) were homozygous PSV carriers, and 17 (0.25%) were DH PSV carriers. Mean age at diagnosis of any cancer among single PSV age was 46.8 ± 14.9 years and among DH PSV carriers 37.6 ± 13.0 years (P < 0.0001). Notably, age at diagnosis for breast cancer among single BRCA1 PSV carriers (n = 59) was 43.8 ± 8.7 years (p = 0.7606), among single BRCA2 PSV carriers (n = 52)—47.9 ± 13.0 years (p = 0.2274) compared with 42.3 ± 13.0 years among DH PSV carriers (n = 10- 9 of whom were carriers of either BRCA1 or BRCA2).ConclusionDH for PSV in two cancer susceptibility genes is a rare event, and the mean age at cancer diagnosis is younger in DH PSV carriers compared with single PSV carriers.

259

项与 BRCA2 相关的新闻（医药）

2024-10-30

·PRNewswire

Helix to Showcase the Impact of Clinico-Genomic Research on Clinical Care and Drug Discovery at ASHG Annual Meeting

Helix reveals new research developments in a wide range of therapeutic areas at the American Society of Human Genetics 2024 Annual Meeting SAN MATEO, Calif., Oct. 30, 2024 /PRNewswire/ -- Helix, a leader in population genomics and precision health, will unveil new clinical research and deliver a range of platform talks that continue to underscore the power of genomic insights at the ASHG 2024 Annual Meeting from November 5-9, 2024, in Denver, Colorado. Presentations include the latest findings from Helix and collaborators, detailing new data on predictors of future risk for cardiovascular disease, genetic and metabolic factors associated with weight loss while on semaglutide, the impact of foregoing routine pharmacogenetic testing on major adverse events and more. With these insights, health system and life science researchers can conduct innovative studies in a wide range of therapeutic areas to drive drug discovery and development, improve pharmacogenomic testing, identify disease risk and more. "Our growing library of research continues to highlight the transformative potential of genomics in advancing the field of precision health," said William Lee, Ph.D., chief science officer at Helix. "By offering data-driven insights in an ever-growing array of use cases, we are paving the way for more personalized care and therapies that can significantly improve patient outcomes and revolutionize healthcare as we know it." Clinical findings and platform talks will be presented at the conference during the times listed below: Platform Talks Introducing an efficient framework to evaluate oncology and cardiology gene-disease validity leveraging clinicogenomic biobank data Thursday, November 7, 2024, from 10:45-11:00 a.m. MT in Room 405 Presented by Daniela Iacoboni, PhD, Genomics Counselor III Classification of rare nonsynonymous variants to identify individuals at low risk of disease: introducing variants of potential risk Thursday, November 7, 2024, from 11:30-11:45 a.m. MT in the Mile High Ballroom 2&3 Presented by Alexandre Bolze, PhD, Principal Scientist Weight loss with semaglutide is influenced by traditional metabolic risk factors and BMI-associated genetic variants Friday, November 8, 2024, from 11:30-11:45 a.m. MT in Room 501 Presented by Matthew Levy, PhD, Senior Research Scientist Comparing scalable and automated vs. ACMG/AMP variant interpretation strategies for BRCA1 and BRCA2 in a large clinicogenomic cohort from six US-based health systems Friday, November 8, 2024, from 1:45-2:00 p.m. MT in the Four Seasons Ballroom 4 Presented by Kelly Schiabor Barrett, PhD, Senior Staff Scientist Finding the pathogenic variant in the haystack: using breast-cancer-related family history from electronic health records to identify patients who should be prioritized for genetic testing Saturday, November 9, 2024 from 10:00-10:15 a.m. MT in Room 505 Presented by Daniel Kiser, MS University of Nevada Reno, School of Medicine Poster Presentations Retrospective study shows pharmacogenomic testing could reduce adverse events associated with clopidogrel use by 38% Wednesday, November 6, 2024, from 2:30-4:30 p.m. MT in the Poster Area (#7017W) Presented by Natalie Telis, PhD, Senior Research Scientist and Nicole Washington, PhD, Director, Product Management Predicting coronary artery disease using an exome-based estimate of KIV-2 repeat count Thursday, November 7, 2024, from 2:30-4:30 p.m. MT in the Poster Area (#5147T) Presented by Natalie Telis, PhD, Senior Research Scientist Discovery of rare coding variants with loss of function effect using a sliding window technique on clinicogenomic data Friday, November 8, 2024, from 2:30-4:30 p.m. MT in the Poster Area (#4041F) Presented by Liz Cirulli, PhD, Associate Director, Research Genetic study of Crohn's disease in the US population Friday, November 8, 2024, from 2:30-4:30 p.m. MT in the Poster Area (#5060F) Presented by Alexandre Bolze, PhD, Principal Scientist and Akwasi Asabere, PhD, Executive Advisor To join Helix at ASHG and learn more about the company's clinico-genomic programs empowering innovative precision therapies, please visit booth #970. About Helix: Helix is the leading population genomics and precision health organization. Helix enables health systems, life sciences companies and payers to accelerate the integration of genomic data into patient care and therapeutic development. Learn more at . Media Contact: [email protected] SOURCE Helix WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床研究

2024-10-29

·PRNewswire

Discovery of cancer risk associations for six novel genes

REYKJAVIK, Iceland, Oct. 29, 2024 /PRNewswire/ --Scientists at deCODE genetics/Amgen, and their collaborators have discovered six novel genes with rare germline variants that associate with cancer risk. The findings are published today in Nature Genetics under the title "Gene-based burden tests of rare germline variants identify six cancer susceptibility genes". Continue Reading Kari Stefansson senior author of the paper, “Gene-based burden tests of rare germline variants identify six cancer susceptibility genes”, published today in Nature Genetics, discusses the paper with Erna V. Ivarsdottir first author on the paper. Kari Stefansson CEO of deCODE genetics and senior author on the paper in Nature Genetics, with Erna V. Ivarsdottir scientists at deCODE genetics and first author. A subset of cancers arises in individuals who are born with rare sequence variants that significantly alter their cancer risk. The discovery of such variants, like those in the BRCA1- and BRCA2 genes, has led to improved early cancer detection and the development of targeted therapies, ultimately reducing the cancer burden and improving prognosis of those carrying these mutations. In this study, the scientists analysed three large genetic datasets from individuals of European descent, including 130,991 cancer patients and 733,486 controls. Through a gene-based burden association analysis across 22 different cancer types, they found four novel genes associated with a risk of developing cancer; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer, and CMTR2 for both lung cancer and cutaneous melanoma. The relative increase in cancer risk conferred by these variants was substantial (90-295%), but it should be noted that the design of the study does not allow accurate assessment of absolute lifetime cancer risk. Additionally, the researchers found the first genes with rare variants that are associated with a decreased risk of cancer. Specifically, loss of AURKB was found to protect against any cancer type, and loss of PPP1R15A was associated with 53% lower risk of breast cancer. This suggests that inhibition of PPP1R15A may be a therapeutic option for breast cancer. The study revealed new insight into the biological mechanisms involved in cancer predisposition that will hopefully lead to better screening and treatment strategies. Video - Photo - SOURCE deCODE genetics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

2024-10-19

·今日头条

【Cell 子刊】绍兴市人民医院：乳腺癌新的生物标志物和治疗靶点

【导读】染色体外环状DNA （extracchromosomal circular DNA, eccDNAs）是由环状和可移动DNA分子组成的不同基因组实体，但其在乳腺癌（breast cancer， BC）中的分子功能和影响尚不清楚。 10月16日，绍兴市人民医院研究团队在期刊《Cell Reports》上发表了研究论文，题为“Genome-wide characterization of extrachromosomal circular DNA in breast cancer and its potential role in carcinogenesis and cancer progression”，本研究使用Circle-seq分析了19例BC组织和17例癌旁正常组织的eccDNAs。研究人员发现eccDNA存在于所有染色体上，并富集在与BC通路相关的7个eccDNA热点基因（HSGs）中。研究人员发现了几个包含完整基因的eccDNAs （ecgenes）和包含miRNAs的eccDNAs (ecmirs)，它们与癌症相关通路相关。合成的eccMIR6748、ecmir6508和ecmir3142可上调MCF-7细胞中miRNA的表达，其中ecmir6748通过上调miR-6748在转录后水平抑制肿瘤抑制候选因子5 （TUSC5）促进BC细胞的迁移和侵袭。此外，eckmir6748还通过p38丝裂原活化蛋白激酶（MAPK）信号通路影响BC的进展。这些发现表明，包含功能性基因组片段的eccDNAs在BC的起始和进展中发挥作用，提供了基因组可塑性的动态来源和作为生物标志物和治疗靶点的潜力。 https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01196-3 背景信息 01 乳腺癌是全球女性肿瘤相关死亡的主要原因，每年约有230万新病例报告。它是一种复杂和高度异质性的疾病，受遗传学的强烈影响，并由不同的亚型组成。目前，有多种生物标志物用于BC的分子分型，包括病理学标志物[雌激素受体（ER）、孕激素受体（PR）、人表皮生长因子受体2 （HER2）、Ki-67]、癌基因体细胞突变（BRCA1、BRCA2、PIK3CA等）和免疫标志物（肿瘤浸润淋巴细胞、PD-L1等），BC的分子分型为精准医学提供了靶向治疗、免疫治疗和耐药预测的可能。然而，尽管取得了这些进展，BC患者的临床结局仍然欠佳，这强调了我们需要更好地了解这种疾病的分子特征。染色体外环状DNA （ecDNA）于1964年首次在野猪精子和小麦胚胎中发现，之后被发现广泛存在于从酵母到人类的真核生物中。它是一种可以从线性染色体移动的环状DNA分子。eccDNAs可起源于基因组中的任何地方，并可根据其来源、大小、序列和其他特征进行分类。这些分类包括线粒体环状DNA （mtDNA）、双微体染色体（DMs）、染色体外DNA （ecDNA）、微小DNA （microDNA）等。虽然eccDNA片段的长度差异很大，从约100个碱基对（bp）到兆碱基大小，但大多数eccDNA的大小很小（<500 bp），以前称为微小DNA。这些组件随机产生于核基因组的所有区域，可以包含从小的非编码区到整个基因的任何基因组组件，使其与染色体DNA同源。然而，由于缺乏可识别的着丝粒，eccDNA在细胞有丝分裂过程中不均匀地分离到两个子细胞中。这种不均匀的分离与细胞异质性、肿瘤进展或转移以及耐药密切相关。 eckmir6748通过上调miR-6748促进BC细胞的迁移和侵袭 02 由于miR6748在ddPCR中表现出最高的增强miRNA表达，研究人员进一步研究了eccMIR6748与BC的相关性。首先，迁移实验进一步表明，转染ecmcmir6748后，MCF-7细胞的迁移和侵袭能力增加。为了评估过表达miR-6748对MCF-7细胞增殖的影响，研究人员进行了EDU实验，但未观察到明显的变化。 eckmir6748通过上调miR-6748促进BC细胞的迁移和侵袭为探究eccmri6748在乳腺癌中致癌活性的分子机制，研究人员应用TargetScan和MicroT-CDS预测miR-6748与其靶基因的相互作用概率。研究人员预测出501个靶基因为miR-6748的靶基因，并利用TissGDB数据库进一步筛选BC的特异性表达基因，发现只有一个基因tusc5 （tumor suppressor candidate factor 5）与BC相关。GEPIA工具进一步分析显示TUSC5在BCTs中的表达显著低于对照组。同时，通过TargetScan数据库预测TUSC5与miR-6748的相互作用，双荧光素酶报告基因分析显示，与MCF-7/阴性对照（NC） WT组相比，MCF-7/miR-6748野生型（WT）组的相对发光活性显著降低。为了证实TUSC5与miR-6748的相互作用，研究人员合成了TUSC5-3- utr - wt和TUSC5-3- utr -MUT（突变体），相互作用区域的破坏极大地阻碍了TUSC5-3- utr -MUT与miR-6748的相互作用，结果显示MCF-7/NC MUT组与MCF-7/miR-6748 MUT组之间没有明显差异。研究人员进一步研究了这种相互作用，发现在miR-6748过表达时，TUSC5蛋白的表达被显著抑制，在miR-6748过表达时，TUSC5蛋白的表达被显著上调。虽然miR-6748水平的变化不影响TUSC5 mRNA的表达，但研究结果推测TUSC5在转录后水平受到miRNAs的调控。因此，这些结果表明，eccMIR6748通过上调miR-6748调控BC细胞的迁移和侵袭能力。 ecmir6748在BC细胞中促进肌动蛋白聚合 03 为了验证eccMIR6748表达的增加是否通过增强F-actin聚合来促进MCF-7细胞的趋化作用，研究人员进行了F-actin聚合实验。结果表明，表皮生长因子（EGF）可诱导ecmir6748 /MCF-7细胞在2 min和15 s时F-actin聚合增加。在eccMIR6748/MCF-7细胞中，肌动蛋白聚合显著增加，表明eccMIR6748在细胞骨架重排中的重要作用。免疫荧光染色检测了f -肌动蛋白水平。EGF诱导了ecmir6748 /MCF-7细胞中F-actin含量的增加，而Scr/MCF-7细胞中没有。随后，研究人员研究了ecmir6748是否通过p38 MAPK信号通路影响癌细胞。研究显示，过表达eccMIR6748显著增加p-p38的表达。此外，在EGF刺激2 min后，p-p38的表达显著增加。而JAK2的表达不受eccMIR6748的影响。接下来，研究人员使用p38 MAPK抑制剂SB203580来验证结果。用SB203580处理MCF-7细胞后，eccMIR6748组p-p38蛋白水平显著降低。然后，研究人员研究了eccMIR6748是否通过p38 MAPK信号通路影响LIMK/cofilin。LIMK和cofilin是参与F-actin动态调控的两个关键因子。研究显示，eccMIR6748的表达增加促进了LIMK和丝切蛋白的磷酸化，p-p38的表达增加也是如此。综上所述，这些研究结果表明，MCF-7细胞中eccMIR6748的表达增加通过调节LIMK/cofilin的磷酸化来促进显著的细胞骨架重塑。【参考资料】 https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01196-3 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 线上｜10月22日 ▶ 代谢组学在精准医学方向的研究应用线上高峰论坛 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会 🕓 上海｜11月21日-24日 ▶ 第七届上海国际肿瘤内科学论坛 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会点击对应文字查看详情