Integration of Genetic and Epigenetic Alterations in the Discovery of Molecular Drivers of Malignancy in Glioma

Smith, Ashley A.

Full Metadata

Overview

Year:: 2014
Contributor:: Smith, Ashley A (creator); Kelsey, Karl (Director); Marsit, Carmen (Reader); Houseman, E. Andres (Reader); Huang, Yen-Tsung (Reader); Wiencke, John (Reader); Brown University. BIOMED: Pathobiology (sponsor)
Genre:: theses
Subject:: DNA methylation; IDH1; Gliomas; Epigenetics; DNA--Methylation
Extent:: xiv, 177 p.
DOI: https://doi.org/10.7301/Z0PR7TBX

Files

Description

Abstract:: Gliomas are a family of extremely aggressive brain cancers, which, despite current treatment options, have poor prognoses. There are distinct subtypes of gliomas, and accurately identifying these is critical for diagnosis and management. Often, the pathologic diagnosis of these subtypes is difficult, and research is underway to discover novel biomarkers that aid in accurate subtype identification and prognostication. This thesis focuses on the joint analysis of DNA methylation profiles with somatic mutation and gene expression data in glioma, assessing the nature of their association with each other and, subsequently, with histology and disease outcome. The ultimate goal is to develop potential prognostic biomarkers of the disease. DNA methylation was determined for several different grades and histologies of glioma in addition to non-brain-tumor controls. The same samples were sequenced for IDH1/2 mutations. We, and others, discovered an IDH hypermethylator phenotype, showing a tight association between the occurrence of IDH mutation and hypermethylation. This phenotype had a higher prevalence in low-grade and secondary gliomas. Besides mutation, DNA methylation is also associated with other somatic alterations, which can alter gene expression. To better understand how DNA methylation and gene expression drive glioma, we used an integrative bioinformatics approach; our goal was to investigate DNA methylation that modulates gene expression as well as independent DNA methylation (methylation that may exert its phenotypic effects through alternative mechanisms), assessing the nature of their association with disease survival. Our model supports the existing theory that DNA methylation can work through gene expression to influence survival outcome but also suggests that DNA methylation can work alone or through alternative mechanisms to influence glioma outcome. In addition, our approach offers an alternative method of biomarker discovery, which could potentially be used for diagnostic and therapeutic purposes. Overall, this work supports the hypothesis that somatic mutations are not solely responsible for the glioma phenotype. Epigenetics, particularly DNA methylation, is also important in both the genesis and outcome of the disease. Furthermore, our model provides an alternative approach for biomarker discovery that may also be applicable to cancers other than glioma.
Notes:: Thesis (Ph.D. -- Brown University (2014)

Content

Access Conditions

Rights: In Copyright
Restrictions on Use: Collection is open for research.

Citation

Smith, Ashley A., "Integration of Genetic and Epigenetic Alterations in the Discovery of Molecular Drivers of Malignancy in Glioma" (2014). Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z0PR7TBX

Relations

Collection:

Pathobiology Theses and Dissertations

Theses and Dissertations for the Pathobiology department.
...