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.

项目总结/摘要 肿瘤治疗不能获得持久的缓解通常归因于肿瘤内的异质性 (ITH)这促进了肿瘤的进化和耐药克隆的产生。历史上， 通过基因组改变如体细胞突变和拷贝数改变来评估。最近的研究 表明表观基因组ITH也可能有助于肿瘤演变和治疗抗性。但 表观基因组ITH的患病率和程度还不清楚。低级别胶质瘤（LGG），包括 II级星形细胞瘤和II级少突胶质细胞瘤是通过手术切除治疗的缓慢生长的肿瘤， 在某些情况下，还需要放疗和替莫唑胺化疗。这些肿瘤不可避免地会复发， 星形细胞瘤和III级少突胶质细胞瘤，或IV级继发性胶质母细胞瘤。LGG的特点是 通过异柠檬酸脱氢酶（IDH）基因的克隆突变，驱动癌代谢产物D- 2-羟基戊二酸（2 HG），并导致表观基因组改变，包括神经胶质瘤CpG的发展 岛甲基化表型（G-CIMP）。我们实验室公布的数据和这里提供的初步数据 表明IDH突变型胶质瘤的表观基因组在空间上不同的肿瘤区域显示ITH， 显示了随时间的演变在这个提议中，我们将测试中心假设，即表观基因组ITH是一个特征， 具有生物学和临床意义的IDH突变型胶质瘤。对于IDH突变型胶质瘤患者的队列， 我们将使用一种新的地形学方法在三维空间中描述ITH的特征，这种方法是在 与神经外科医生、神经病理学家和生物医学成像专家合作。我们会分析DNA 甲基化和染色质可及性，两种互补的方法来表征 细胞的表观基因组状态。在目标1中，我们将研究表观基因组ITH相对于 基因组ITH。在目标2中，我们将通过研究表观基因组ITH的生物学意义来确定其在肿瘤中的作用。 与基因调控的关系。在目标3中，我们将通过以下方法确定表观基因组ITH的临床意义： 研究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ITH的最全面表征。获得的知识 这些研究将加深我们对表观基因组ITH对肿瘤演变的贡献的理解， 治疗耐药性，最终指导设计新的和改进的方法， 治疗失败这项研究的结果也可能直接影响IDH治疗的临床实践。 通过支持在神经胶质瘤分级和诊断中使用表观基因组标记， 指导使用免疫治疗药物和生物标志物进行患者分层。