A comprehensive study of extrachromosomal circular DNA in pancreatic ductal adenocarcinoma

Schreyer, Daniel (2024) A comprehensive study of extrachromosomal circular DNA in pancreatic ductal adenocarcinoma. PhD thesis, University of Glasgow.

Abstract

Introduction:

Extrachromosomal circular DNAs (eccDNA) vary in sizes and drive many aspects of tumour biology, including drug resistance and oncogene amplification. However, little is known about their landscape, role, and association with specific features of cancer in pancreatic ductal adenocarcinoma (PDAC).

Approach:

To better understand their properties in PDAC, I combine multiple sources of genomic data with transcriptomic data from a large library of PDAC patient-derived organoids (PDOs), including some with matched primary tumours or cell lines, and a panel of PDAC patient derived cell lines.

Results:

Here, I report that large and amplified eccDNAs (ecDNAs) are prevalent in PDAC, revealing a diverse landscape containing PDAC-specific oncogenes. The frequency of tumours harbouring ecDNAs was increased when genomic instability and TP53 alterations were present, suggesting the association of ecDNA occurrence with unstable genomes. Furthermore, integrating experimental work, performed by collaborators at the University of Verona, and computational analysis, ecDNAs were found to drive PDO adaptation to harsh environments.Investigation of the complete eccDNA landscape revealed that eccDNAs predominantly originate from regions with a high gene- and enhancer-density, active transcription, and accessible chromatin. I identified 61 recurrent eccDNA hotspots associated with increased transcription suggesting a direct link between transcription and eccDNA formation. Finally, as eccDNA analysis involves the use of multiple tools, I present nf-core/circdna, an open-source workflow that integrates the tools of eccDNA research and data processing. This workflow offers ease of use, portability, comprehensive documentation and full reproducibility.

Conclusions:

EccDNAs are an important feature of PDAC genomic. This in-depth characterisation of multiple features of eccDNAs provides a comprehensive overview of their properties in PDAC and a valuable resource for future research, hopefully uncovering potential avenues for eccDNA-based precision medicine.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Funder's Name: European Commission (EC)
• Supervisor's Name: Bailey, Dr. Peter
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84412
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 Jun 2024 11:01
• Last Modified: 27 Jun 2024 12:48
• Thesis DOI: 10.5525/gla.thesis.84412
• URI: https://theses.gla.ac.uk/id/eprint/84412

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