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Genomic characterization of therapeutically-relevant targets in progressive/ high-grade meningioma

进行性/高级别脑膜瘤治疗相关靶点的基因组特征

基本信息

批准号：
401837860
负责人：
Professor Dr. Tareq Juratli
金额：
--
依托单位：
Klinik und Poliklinik für Neurochirurgie
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至无数据
项目状态：
未结题

来源：
https://gepris.dfg.de/gepris/projekt/401837860?language=en
关键词：
Genomic characterization therapeutically relevant targets

项目摘要

Meningiomas are the most common primary intracranial tumor. Although many of these tumors are benign, and are cured with the standard therapies of surgical resection and radiation therapy, recurrence is nevertheless relatively common. After failure of frontline treatment, there is unfortunately no current standard therapy to offer patients who have progressive recurrent meningioma, and securing durable, long-term disease control in this setting has been challenging. New therapeutic approaches are needed for these cases. Modern genomic technologies have allowed for broad characterization of somatic gene mutations found in tumor cells in many different cancers. Recent work has identified SMO, AKT1, KLF4 and TRAF7 mutations in low-grade meningiomas, in addition to the well-established NF2 inactivation that is characteristic of this neoplasm. On the other hand, higher-grade and recurrent meningiomas harbor more frequently (up to 28%) TERT promoter (TERTp) mutations, which are predictive of a higher recurrence rate. However, a longitudinal genomic analysis of driver genetic alterations across the spectrum of initial and recurrent disease remains incomplete. In our proposed project, we will focus on understanding the molecular alterations across the clinical spectrum of recurrent meningiomas. Therefore, we characterized a large cohort of patients (n= 120) with progressive/higher-grade meningiomas at both initial diagnosis and recurrence. After pursuing the whole exome sequencing in matched initial and recurrent meningioma pairs, we analyzed the data by established algorithms to evaluate for somatic mutations, copy number alterations and rearrangements. We discovered new interesting candidate genes that we are validating by an orthogonal approach using focused Sanger sequencing and single-nucleotide genotyping. In addition, to confirm our findings, we are performing immunohistochemistry and western blot in large number of samples. Using proliferation and clonogenic assays in models that include meningioma cell lines (e.g. IOMM-Lee), patient-derived meningioma cell lines we have established (MN3 and MN8) and TERT-immortalized non-transformed human arachnoid cells, we will functionally characterize the most significant candidate genes and assess their potential for neoplastic transformation. Deleted or amplified genes in recurrent meningiomas, compared to primary meningiomas, will be genetically over-expressed or silenced, respectively, to determine if that results in an altered phenotype in these models. Our proposed genomic and biological analyses have the potential to identify the genetic factors that drive meningiomas to relapse or undergo malignant transformation, targets which could be prioritized to maximize clinical impact. Thus, the successful execution of this work will provide important information to facilitate the design and interpretation of ongoing clinical trials for recurrent progressive meningiomas.

脑膜瘤是最常见的颅内原发肿瘤。虽然这些肿瘤中许多是良性的，可以通过手术切除和放射治疗等标准治疗方法治愈，但复发仍然相对常见。在一线治疗失败后，不幸的是，目前还没有标准的治疗方法来为患有进行性复发脑膜瘤的患者提供治疗，在这种情况下确保持久、长期的疾病控制一直是具有挑战性的。这些病例需要新的治疗方法。现代基因组技术已经能够广泛地表征在许多不同癌症的肿瘤细胞中发现的体细胞基因突变。最近的工作已经在低级别脑膜瘤中发现了SMO、AKT1、KLF4和TRAF7突变，以及这种肿瘤特有的NF2失活。另一方面，高级别和复发的脑膜瘤存在更频繁的TERT启动子(TERTp)突变(高达28%)，这预示着更高的复发率。然而，对初发和复发疾病谱系中的司机基因改变的纵向基因组分析仍然不完整。在我们提出的项目中，我们将重点了解复发性脑膜瘤临床范围内的分子变化。因此，我们描述了一大群进展性/高级别脑膜瘤患者(n=120)的初始诊断和复发情况。在对匹配的初发和复发脑膜瘤对进行完整的外显子组测序后，我们通过建立的算法分析了数据，以评估体细胞突变、拷贝数改变和重排。我们发现了新的有趣的候选基因，我们正在通过使用聚焦Sanger测序和单核苷酸基因分型的正交法进行验证。此外，为了证实我们的发现，我们正在对大量样本进行免疫组织化学和蛋白质印迹。在包括脑膜瘤细胞系(例如IOMM-Lee)、我们建立的患者来源的脑膜瘤细胞系(MN3和MN8)以及TERT永生化的未转化的人类蛛网膜细胞的模型中使用增殖和克隆分析，我们将从功能上表征最重要的候选基因，并评估它们转化为肿瘤的可能性。与原发脑膜瘤相比，复发脑膜瘤中缺失或扩增的基因将分别在基因上过度表达或沉默，以确定这是否会导致这些模型中的表型改变。我们提出的基因组和生物学分析有可能确定驱动脑膜瘤复发或经历恶变的遗传因素，这些目标可以优先考虑，以最大限度地发挥临床影响。因此，这项工作的成功实施将为设计和解释正在进行的复发性进行性脑膜瘤临床试验提供重要信息。