Date Thesis Awarded

5-2015

Document Type

Honors Thesis

Degree Name

Bachelors of Science (BS)

Department

Neuroscience

Advisor

Matthew Wawersik

Committee Member

Oliver Kerscher

Committee Member

Robin Looft-Wilson

Abstract

Cancer is the leading cause of non-accidental death in children. Pediatric ependymomas (PE) are the third most common brain tumor in children. Despite advances leading to better survival outcomes in some cancers, these tumors remain incurable in up to 45% of patients, with recurrent local relapse being the major cause of mortality[18, 19]. Surgical resection is currently the most effective treatment, but over 50% of children whose tumors have been totally resected will still experience tumor recurrence despite aggressive adjuvant therapy [22]. Key molecular events in the pathogenesis of PE have yet to be defined, and understanding these events are proving to be increasingly necessary to developing clinically-relevant applications. In particular, errors in epigenetic regulatory machinery appear to play a substantial role in the pathogenesis of numerous cancers. As such, this research used gene expression profiling data on a large cohort (n=102) of PE samples to search for potential driving mechanisms underlying recurrence and poor prognosis in this cancer. Through this, we developed a model for the role of the histone modifying enzyme SUV4-20H2 in carcinogenesis. SUV4-20H2 confers modifications that lead to chromatin compaction and resultant silencing of genes in component/surrounding DNA. We hypothesized that this enzyme acts to directly regulate proto-oncogenes and that its loss in this cancer leads to their increased expression. We find evidence to support this model for SUV4-20H2 regulation of TERT, the catalytic subunit of telomerase. This holds significant translational value as TERT is strongly associated with recurrence and has been shown to increase tumorigenicity of tumor initiating cells, and a better understanding of it's regulation could lead to development of new therapies. Additionally, these findings implicate a potential broader role of SUV4-20H2 in driving carcinogenesis and warrant further investigation.

Available for download on Monday, May 14, 2018

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