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Mouse Modeling and Epigenomic Profiling of Clear Cell Sarcoma
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Mouse Modeling and Epigenomic Profiling of Clear Cell Sarcoma
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Dissertation
Mouse Modeling and Epigenomic Profiling of Clear Cell Sarcoma
2023
Overview
Clear cell sarcoma (CCS) is a rare malignancy that occurs around tendons or aponeuroses of the extremities. In about 90% of cases, CCS is driven by a chromosomal translocation between chromosomes 22 and 12 that generates a fusion gene between EWSR1 and ATF1. The translated EWSR1-ATF1 (EA1) oncoprotein functions as a nucleus-localized factor to epigenetically reprogram transcription into a cancerous state. However, the precise roles of EA1 in driving CCS are largely unknown. The utilization of robust mouse models and next-generation sequencing revealed the functional genomic landscape of CCS and the epigenomic profile of the EA1 oncoprotein. Copy number alterations, including amplifications of chromosomes 7 and 8, were identified in human CCS tumors. Secondary genetic alterations, such as MYC hyperactivation, were recapitulated in the mouse model to demonstrate they can impact tumor growth and phenotype. Lastly, epigenomic profiling revealed previously uncharacterized functions of EA1 and epigenetic regulatory regions shared between human and mouse CCS. Sarcoma subtypes driven by a chromosomal translocation are understudied and preferentially affect pediatric populations. Understanding the genomic landscape and the fusion oncoprotein functions that drive these cancers are crucial to improve therapies.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9798380130370
