Characterization of genomic subtypes of Ewing sarcoma based on copy number alterations

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Title Characterization of genomic subtypes of Ewing sarcoma based on copy number alterations
Publication Type dissertation
School or College School of Medicine
Department Oncological Sciences
Author Gardiner, Jamie Diane
Date 2018
Description Ewing sarcoma is the second most common bone cancer in children, with an incidence of 3 cases per million people in the United States. The 5-year survival for patients with primary tumors is approximately 70%, while 5-year survival for patients with metastasis at the time of diagnosis is less than 30%. These numbers have not improved over the past 3 decades, suggesting a need for superior therapies and a better understanding of the molecular pathogenesis of this disease. Ewing sarcoma is characterized by an EWS-ETS translocation, which functions as an aberrant and oncogenic transcription factor. Like other translocation-driven cancers, point mutations are infrequent in Ewing sarcoma. The more frequent and recurring genetic aberration in Ewing sarcoma, aside from the EWS-ETS translocation, is copy number alteration (CNA). This dissertation characterizes two genomic subtypes of Ewing sarcoma based on CNAs: simple (containing CNAs in <1% of the length of the genome), and complex (containing CNAs in ≥1% of the length of the genome). Our data show that the complex subtype trends toward worse outcome than the simple subtype. We further explore specific genes and pathways that are altered by CNAs in the complex subtype of Ewing sarcoma, including the TP53 pathway, CEBPB, and HOTAIR. Although occurring in only 5% of Ewing sarcoma cases, TP53 mutations are tightly associated with the complex subtype. We test the functional consequences of TP53 mutations in Ewing sarcoma cell lines and observe that TP53 mutant cell lines are iv resistant to chemotherapeutic drugs and radiation. We also explore alternate mechanisms of p53 pathway suppression through CNAs of p53 pathway members CDKN2A, MDM2, and MDM4. Copy number gain of CEBPB occurs in 15% of Ewing sarcoma. We demonstrate how CEBPB acts as an oncogene by promoting attachment-independent cell growth, resistance to chemotherapeutic drugs, and regulation of the cancer stem cell marker ALDH1A1. HOTAIR is a long non-coding RNA that is upregulated and unmethylated in the genomically complex Ewing sarcoma subtype. We demonstrate that Ewing sarcoma cells deficient in HOTAIR have increased cell growth, viability, and migration, and we propose future studies to understand the exact mechanisms through which HOTAIR is involved in these processes.
Type Text
Publisher University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Rights Management (c) Jamie Diane Gardiner
Format application/pdf
Format Medium application/pdf
ARK ark:/87278/s65r0tw7
Setname ir_etd
ID 1694260
Reference URL https://collections.lib.utah.edu/ark:/87278/s65r0tw7
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