Loss of oncogene insulation drives IDH1 mutant glioma

Massachusetts General Hospital, Boston MA

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Abstract

? 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.