Bailey, Christopher; (2024) The prevalence, mutagenesis and evolution of focal copy number amplifications and extrachromosomal DNA in cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Extrachromosomal DNA (ecDNA) is a circular genomic structural variant in tumour cells that facilitate high levels of oncogene focal copy number amplification through unequal segregation of ecDNA structures during mitosis. This contributes to intra-tumour heterogeneity from which competition and selection can occur, however the mutagenesis, evolution, and clinical implications of focal amplifications and ecDNA in cancer remain largely understudied. This thesis details the prevalence and classification of ecDNA across various tumour subtypes. Through the analysis of a large dataset comprising 15,832 samples from 14,778 patients and 39 tumour types, the study revealed a comprehensive body map of ecDNA frequency and contents. In addition to oncogene-enriched ecDNA-driven focal amplifications we discovered non-oncogene-containing ecDNA, which exhibited enrichment for immunomodulatory genes. These immunomodulatory ecDNA were associated with reduced T cell infiltration. Mutational processes such as deamination clock-like, tobacco smoking, and APOBEC cytidine deaminase activity were linked to the presence of ecDNA, while MMRd and POLD1/POLE deficiency signatures showed negative correlation. Moreover, treatment induced mutations were found to have occurred prior to ecDNA formation. The TRACERx dataset was then utilised to investigate the evolutionary aspects of ecDNA and focal amplifications in non-small cell lung cancer (NSCLC), exploring the nature of focal amplifications and their transcriptional activity using whole exome and RNA sequencing data. Spatial and longitudinal sampling revealed the enrichment of ecDNA during tumour progression including at autopsy. The association between ecDNA presence and disease stage, metastatic disease, and overall survival in multiple tumour types was then quantified, demonstrating that ecDNA presence is associated with poor prognosis and late-stage disease, independent of underlying genomic instability. Finally, case studies reveal novel links between ecDNA and treatment resistance.

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