Loss of oncogene insulation drives IDH1 mutant glioma

癌基因绝缘的丧失导致 IDH1 突变神经胶质瘤

• 批准号: 9050912
• 负责人: William Alexander Flavahan
• 金额: $ 5.61万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050912
• 关键词: Age; Area; Automobile Driving; Binding; Brain; Brain Neoplasms; CCCTC-binding factor; Characteristics; Chromatin Loop; Chromosomal translocation; Chromosomes; Clinical; Complex; Cytosine; DNA; DNA Methylation; DNA Sequence; Data; Development; Diagnosis; Dioxygenases; Disease; Distal Enhancer Elements; Elements; Enhancers; Enzymes; Epigenetic Process; Family; Functional disorder; GFI1 gene; Gene Activation; Gene Expression; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genome; Genomics; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; Growth and Development function; Housekeeping; Housekeeping Gene; Hypermethylation; Isocitrate Dehydrogenase; Lead; Life; Malignant Neoplasms; Metabolic; Methylation; Modeling; Mutation; Oncogenes; Oncogenic; PDGFRA gene; Patients; Phenotype; Proteins; Receptor Activation; Receptor Protein-Tyrosine Kinases; Reporting; Research; Resistance; Site; Specificity; Structure; Testing; Therapeutic Human Experimentation; Treatment Failure; Tumor Suppressor Genes; Tyrosine-Kinase Oncogenes; anticancer research; cancer diagnosis; design; gene interaction; mutant; neoplastic cell; novel; oncology; outcome forecast; public health relevance; receptor; segregation; three dimensional structure; tumor; tumor growth

 DESCRIPTION (provided by applicant) Gliomas remain one of the foremost challenges in oncology due to their dismal clinical prognosis and resistance to treatment. A subset of glioma, characterized by a DNA hypermethylation phenotype, appears to be caused by a mutation in the metabolic enzyme Isocitrate Dehydrogenase 1 (IDH1). While the DNA hypermethylation may be responsible for silencing tumor suppressor genes, there has still not yet been a description of a consistent activated or altered tumor-driving oncogene in hypermethylator tumors, in contrast to the high rate of receptor tyrosine kinase (RTK) amplification or mutation in IDH1-wild type glioblastoma. In the absence of a genetic activation of these genes, it is possible that the DNA hypermethylation epigenetically activates an oncogene. DNA methylation is known to inhibit binding to DNA of the insulator protein CTCF. Insulator complexes control the three dimensional structure of the genome and restrict the targeting of enhancer elements. Enhancers can drive gene expression, and genetic translocations which cause enhancers to drive oncogenes are known to cause some kinds of cancers. The goal of this research is to test the hypothesis that the IDH1 hypermethylator phenotype disrupts the genetic insulation surrounding and protecting the RTK and oncogene PDGFRA. Once this insulation is lost, a nearby housekeeper enhancer begins interacting with and driving expression of PDGFRA, causing tumor growth and development. This phenomenon, which may also drive other cancers, occurs without any underlying genetic insult to the area, and as such would not be detected by an analysis looking for mutations or copy number aberrations.

 描述（由申请人提供）由于其令人沮丧的临床预后和对治疗的抗性，胶质瘤仍然是肿瘤学中最重要的挑战之一。胶质瘤的一个子集，其特征在于DNA高甲基化表型，似乎是由代谢酶异柠檬酸脱氢酶1（IDH 1）的突变引起的。虽然DNA高甲基化可能是导致肿瘤抑制基因沉默的原因，但与高甲基化肿瘤中受体酪氨酸激酶（RTK）扩增或突变的高比率相反，在高甲基化肿瘤中仍然没有一致的激活或改变的肿瘤驱动癌基因的描述。 IDH 1-野生型胶质母细胞瘤。在这些基因缺乏遗传激活的情况下，DNA超甲基化可能表观遗传地激活癌基因。已知DNA甲基化抑制绝缘子蛋白CTCF与DNA的结合。绝缘子复合物控制基因组的三维结构并限制增强子元件的靶向。增强子可以驱动基因表达，并且已知导致增强子驱动癌基因的遗传易位会导致某些类型的癌症。本研究的目的是检验IDH 1超甲基化表型破坏周围的遗传绝缘和保护RTK和癌基因PDGFRA的假设。一旦失去这种绝缘，附近的管家增强子开始与PDGFRA相互作用并驱动其表达，导致肿瘤生长和发展。这种现象也可能导致其他癌症，发生时不会对该区域造成任何潜在的遗传损伤，因此不会通过寻找突变或拷贝数畸变的分析来检测。