Loss of oncogene insulation drives IDH1 mutant glioma

 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拒，胶质瘤仍然是肿瘤学中最重要的挑战之一。以DNA高甲基化表型为特征的一组胶质瘤，似乎是由代谢酶异柠檬酸脱氢酶1(IDH1)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，但目前还没有关于高甲基化肿瘤中一致的激活或改变的致癌基因的描述，这与受体酪氨酸激酶(Rtk)扩增或突变的高比率形成对比。 IDH1-野生型胶质母细胞瘤。在缺乏这些基因的遗传激活的情况下，DNA超甲基化有可能在表观上激活癌基因。已知DNA甲基化可抑制绝缘蛋白CTCF与DNA的结合。绝缘体复合体控制基因组的三维结构，限制增强子元件的靶向。增强剂可以驱动基因表达，而导致增强剂驱动癌基因的基因易位已知会导致某些类型的癌症。本研究的目的是验证IDH1高甲基化表型破坏RTK和癌基因PDGFRA周围的遗传隔离和保护的假说。一旦失去这种绝缘，附近的管家增强子就开始与PDGFRA相互作用并驱动其表达，导致肿瘤的生长和发展。这种现象也可能导致其他癌症，它的发生不会对该区域造成任何潜在的基因侮辱，因此不会被寻找突变或拷贝数异常的分析检测到。

 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.