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Molecular Characterization of Genetic and Epigenetic Alterations in Gliomas

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Date
2012
Author
Duncan, Christopher Gentry
Advisor
Yan, Hai
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Abstract

Glioma development and progression are driven by complex genetic alterations, including point mutations and gain or loss of genomic copy number, as well as epigenetic aberrations, including DNA methylation and histone modifications. However, the molecular mechanisms underlying the causes and effects of these alterations are poorly understood, and improved treatments are greatly needed. Here, we report a comprehensive evaluation of the recurrent genomic alterations in gliomas and further dissect the molecular effects of the most frequently-occurring genomic events. First, we performed a multifaceted genomic analysis to identify genes targeted by copy number alteration in glioblastoma, the most aggressive malignant glioma. We identify EGFR negative regulator, <italic>ERRFI1</italic>, as a glioblastoma-targeted gene within the minimal region of deletion in 1p36.23. Furthermore, we demonstrate that Aurora-A kinase substrate, <italic>TACC3</italic>, displays gain of copy number on 4p16.3 and is overexpressed in a grade-specific pattern. Next, using a gene targeting approach, we knocked-in a single copy of the most frequently observed point mutation in gliomas, <italic>IDH1<super>R132H/WT</super></italic>, into a human cancer cell line. We show that heterozygous expression of the <italic>IDH1<super>R132H</super></italic> allele is sufficient to induce the genome-wide alterations in DNA methylation characteristic of these tumors. Together, these data provide insight on genetic and epigenetic alterations which drive human gliomas.

Type
Dissertation
Department
Pathology
Subject
Pathology
Genetics
Oncology
cancer
epigenetic
genetic
glioma
IDH1
methylation
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https://hdl.handle.net/10161/6115
Citation
Duncan, Christopher Gentry (2012). Molecular Characterization of Genetic and Epigenetic Alterations in Gliomas. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/6115.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

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