Three-dimensional characterization of epigenomic intratumoral heterogeneity in IDH-mutant glioma

IDH 突变胶质瘤表观基因组瘤内异质性的三维表征

• 批准号: 10170314
• 负责人: Radhika Mathur
• 金额: $ 4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170314
• 关键词: 3-Dimensional; Affect; Age; Anatomy; Astrocytoma; Biological; Biological Markers; Biological Process; Brain Neoplasms; Cells; Chromatin; Clinical; Clinical Treatment; Collaborations; CpG Island Methylator Phenotype; DNA; DNA Methylation; DNA Sequence Alteration; DNA methylation profiling; Data; Development; Diagnosis; Diagnostic; Enhancers; Epigenetic Process; Evolution; Excision; Failure; Fostering; Gene Expression Regulation; Generations; Genes; Genomics; Glioblastoma; Glioma; Histologic; Histones; Histopathology; Hypermethylation; Immune; Immunotherapeutic agent; Isocitrate Dehydrogenase; Knowledge; Laboratories; Lateral; MGMT gene; MRI Scans; Magnetic Resonance Imaging; Maps; Medial; Methylation; Molecular; Mutation; Neurosurgeon; Operative Surgical Procedures; Patients; Pattern; Postoperative Period; Prevalence; Primary Neoplasm; Production; Publishing; Radiation; Recurrence; Recurrent tumor; Reporting; Resistance; Sampling; Site; Somatic Mutation; Subcategory; Testing; Time; Treatment Failure; Tumor Volume; Tumor stage; aggressive therapy; base; bioimaging; cancer therapy; chemotherapy; clinical practice; clinically significant; cohort; design; epigenome; epigenomics; exome; genome-wide; improved; individual patient; insight; mutant; novel; oligodendroglioma; patient biomarkers; patient stratification; promoter; response; temozolomide; therapy resistant; three-dimensional modeling; tumor; tumor heterogeneity

Project Summary/Abstract The failure of cancer therapies to achieve durable responses is often attributed to intratumoral heterogeneity (ITH), which fosters tumor evolution and the generation of therapy-resistant clones. ITH has historically been assessed by genomic alterations such as somatic mutation and copy-number alteration. Recent studies suggest that epigenomic ITH may also contribute to tumor evolution and therapy resistance. However, the prevalence and degree of epigenomic ITH are not well understood. Low-grade gliomas (LGGs), which include grade II astrocytoma and grade II oligodendroglioma, are slow-growing tumors treated with surgical resection, and in some cases, with radiation and temozolomide chemotherapy. These tumors inevitably recur as grade III astrocytoma and grade III oligodendroglioma, or as grade IV secondary glioblastoma. LGGs are characterized by clonal mutations in isocitrate dehydrogenase (IDH) genes, which drive production of the oncometabolite D- 2-hydroxyglutarate (2HG) and result in epigenomic alterations including the development of the glioma CpG island methylator phenotype (G-CIMP). Data published by our laboratory and preliminary data presented here indicate that the epigenomes of IDH-mutant gliomas display ITH across spatially distinct tumor regions and show evolution over time. In this proposal, we will test the central hypothesis that epigenomic ITH is a feature of IDH-mutant gliomas that is biologically and clinically significant. For a cohort of IDH-mutant glioma patients, we will characterize ITH in three-dimensional space using a novel topographic approach developed in collaboration with neurosurgeons, neuropathologists, and biomedical imaging experts. We will profile DNA methylation and chromatin accessibility, two complementary approaches towards characterizing the epigenomic state of the cell. In Aim 1, we will investigate the spatial patterning of epigenomic ITH relative to genomic ITH. In Aim 2, we will determine the biological significance of epigenomic ITH by investigating its relationship with gene regulation. In Aim 3, we will determine the clinical significance of epigenomic ITH by investigating its relationship with tumor histologic features and immune cell content, and by investigating ITH of DNA-methylation based biomarkers including MGMT methylation and epigenetic age. Collectively, these studies will provide the most comprehensive characterization of epigenomic ITH to date. Knowledge gained from these studies will deepen our understanding of the contribution of epigenomic ITH to tumor evolution and therapy resistance, ultimately guiding the design of novel and improved approaches towards countering therapy failure. The results of this study may also directly impact clinical practice in the treatment of IDH- mutant glioma by supporting the use of epigenomic signatures in glioma grading and diagnostics and by guiding the use of immunotherapeutics and biomarkers for patient stratification.

项目摘要/摘要 癌症疗法无法实现持久反应的失败通常归因于肿瘤内异质性 （ITH），它促进了肿瘤进化和耐治疗的克隆的产生。历史上一直是 通过基因组改变（例如体细胞突变和拷贝数改变）评估。最近的研究 表明表观基因组学也可能有助于肿瘤的演化和耐药性。但是， 表观基因组学的患病率和程度尚不清楚。低级神经胶质瘤（LGGS），其中包括 II级星形胶质细胞瘤和II级少突胶质瘤是通过手术切除治疗的缓慢生长的肿瘤 在某些情况下，辐射和替莫唑胺化疗。这些肿瘤不可避免地反复出现为III级 星形胶质细胞瘤和III级少突可瘤瘤，或作为IV级胶质母细胞瘤。 LGG是特征的 通过异位酸脱氢酶（IDH）基因中的克隆突变，该基因驱动oncometabolite d-的产生 2-羟基戊二酸（2HG），并导致表观基因组改变，包括神经胶质瘤CpG的发展 岛甲基表型（G-CIMP）。我们的实验室和初步数据发布的数据 表明IDH突变神经胶质瘤的表观基因组在空间不同的肿瘤区域显示ITH， 随着时间的流逝显示进化。在此提案中，我们将测试表观基因组学是一个特征的中心假设 在生物学和临床上具有重要意义的IDH突变神经瘤。对于一组IDH突变的神经胶质瘤患者， 我们将使用在三维空间中使用一种新的地形方法来表征ITH 与神经外科医生，神经病理学家和生物医学成像专家合作。我们将介绍DNA 甲基化和染色质的可及性，两种互补方法用于表征 细胞的表观基因组状态。在AIM 1中，我们将研究表观基因组学ITH的空间图案 基因组ITH。在AIM 2中，我们将通过研究其表观基因组学的生物学意义来确定其生物学意义 与基因调节的关系。在AIM 3中，我们将通过 调查其与肿瘤组织学特征和免疫细胞含量的关系，并通过研究 基于DNA-甲基化的生物标志物，包括MGMT甲基化和表观遗传年龄。总的来说，这些 研究将提供迄今为止表观基因组学的最全面特征。知识获得了 从这些研究中，我们将加深我们对表观基因组学对肿瘤进化和的贡献的理解 耐药性，最终指导新颖和改进的方法的设计 治疗失败。这项研究的结果还可能直接影响临床实践的治疗 突变神经胶质瘤通过支持在神经胶质瘤分级和诊断中使用表观基因组信号以及通过 指导使用免疫疗法和生物标志物进行患者分层。