Molecular Mechanisms of TRAF7 Mutant Aggressive Meningiomas

TRAF7突变侵袭性脑膜瘤的分子机制

• 批准号: 10665542
• 负责人: MURAT GUNEL
• 金额: $ 50.86万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665542
• 关键词: Acute; Adult; Anaplastic Meningioma; Animal Model; Architecture; Automobile Driving; Benign; Benign Meningiomas; Biochemical; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cell Line; Cell Proliferation; Cells; ChIP-seq; Clinical Trials; Code; Collection; DNA Methylation; Deubiquitinating Enzyme; Drug Targeting; Effectiveness; Event; Excess Mortality; Future; Genes; Genital; Genitalia; Genomic approach; Genomics; Glioblastoma; Glioma; Hand; Histologic; Histology; Human; Incidence; Intracranial Neoplasms; Intraneural perineurioma; Invaded; Malignant - descriptor; Meningeal; Mesothelioma; Molecular; Morbidity - disease rate; Mutate; Mutation; NF-kappa B; Neurofibromin 2; Neurologic; Neurologic Deficit; Oncogenic; Operative Surgical Procedures; PIK3CG gene; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Primary Brain Neoplasms; Principal Investigator; Public Health; Radiation; Recurrence; Recurrent tumor; Reporting; Research; Resected; Role; Signal Pathway; Signaling Molecule; Stroke; Structure; Subgroup; Testing; Therapeutic; United States; Untranslated RNA; adenoma; candidate validation; driver mutation; drug efficacy; efficacy testing; epigenomics; exome; exome sequencing; genomic profiles; inhibitor; insight; meningioma; mouse model; mutant; neurovascular; new therapeutic target; next generation sequencing; novel therapeutics; programs; protein function; response; skull base; subcutaneous; transcriptome sequencing; tumor; tumor progression; ubiquitin isopeptidase; ubiquitin ligase; ubiquitin-protein ligase; whole genome

PROJECT SUMMARY / ABSTRACT Meningiomas are the most common primary brain tumors. While typically of benign histology, they can be associated with significant neurological morbidity and have the potential for malignant transformation. In our previous studies, we completed genomic analysis of over 700 meningiomas using whole exome and targeted next-generation sequencing, identifying driver mutations in 12 genes and establishing mutually exclusive molecular subgroups. We now propose to investigate the molecular mechanisms underlying the formation of TRAF7-dependent meningiomas (which represent up to one quarter of all meningiomas), undertake molecular genomic analyses to identify somatic coding and non-coding or genomic events in TRAF7 tumors that progress to higher grades. We also propose to test and validate candidate drug efficacy using primary cultures from surgically resected meningiomas carrying TRAF7 aberrations, as well as mouse models of meningioma that we have established.

项目总结/摘要 脑膜瘤是最常见的原发性脑肿瘤。虽然通常是良性组织学，但它们可以是 与显著的神经系统发病率相关，并具有恶性转化的可能性。在我们 在先前的研究中，我们使用全外显子组完成了700多例脑膜瘤的基因组分析， 下一代测序，确定12个基因中的驱动突变， 分子亚群我们现在建议研究形成的分子机制， TRAF 7依赖性脑膜瘤（占所有脑膜瘤的四分之一）， 分子基因组分析以鉴定TRAF 7肿瘤中的体细胞编码和非编码或基因组事件 这是一个进步到更高的等级。我们还建议使用主要药物来测试和验证候选药物的疗效。 来自携带TRAF 7畸变的手术切除的脑膜瘤的培养物，以及 脑膜瘤。

项目成果

Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

• DOI: 10.1073/pnas.2214997120
• 发表时间: 2023-04-18
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Mishra-Gorur, Ketu;Barak, Tanyeri;Kaulen, Leon D.;Henegariu, Octavian;Jin, Sheng Chih;Aguilera, Stephanie Marie;Yalbir, Ezgi;Goles, Gizem;Nishimura, Sayoko;Miyagishima, Danielle;Djenoune, Lydia;Altinok, Selin;Rai, Devendra K.;Viviano, Stephen;Prendergast, Andrew;Zerillo, Cynthia;Ozcan, Kent;Baran, Burcin;Sencar, Leman;Goc, Nukte;Yarman, Yanki;Ercan-Sencicek, A. Gulhan;Bilguvar, Kaya;Lifton, Richard P.;Moliterno, Jennifer;Louvi, Angeliki;Yuan, Shiaulou;Deniz, Engin;Brueckner, Martina;Gunel, Murat
• 通讯作者: Gunel, Murat