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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要癌症治疗未能实现持久反应通常归因于瘤内异质性（ITH），它促进肿瘤进化和治疗抗性克隆的产生。 ITH 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）进行评估。最近的研究表明表观基因组 ITH 也可能有助于肿瘤进化和治疗耐药性。然而，表观基因组 ITH 的患病率和程度尚不清楚。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生长缓慢的肿瘤，在某些情况下，还需要进行放射治疗和替莫唑胺化疗。这些肿瘤不可避免地会复发，达到 III 级星形细胞瘤和 III 级少突胶质细胞瘤，或 IV 级继发性胶质母细胞瘤。 LGG 的特点通过异柠檬酸脱氢酶 (IDH) 基因的克隆突变，驱动致癌代谢物 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 的发展岛甲基化表型（G-CIMP）。我们实验室发布的数据和此处提供的初步数据表明 IDH 突变神经胶质瘤的表观基因组在空间不同的肿瘤区域中显示 ITH，并且显示随时间的演变。在这个提案中，我们将测试表观基因组 ITH 是一个特征的中心假设 IDH 突变神经胶质瘤的研究具有生物学和临床意义。对于一组 IDH 突变神经胶质瘤患者，我们将使用一种新颖的地形方法在三维空间中描述 ITH 的特征与神经外科医生、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生物学意义。与基因调控的关系。在目标 3 中，我们将通过以下方式确定表观基因组 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 ITH 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最全面的表观基因组 ITH 特征。获得的知识这些研究将加深我们对表观基因组 ITH 对肿瘤进化的贡献的理解治疗耐药性，最终指导设计新颖和改进的对抗方法治疗失败。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特征来识别突变神经胶质瘤指导使用免疫治疗和生物标志物进行患者分层。