Telomere dysfunction and the evolution of the cancer genome

Kearsey, Alexander 2024. Telomere dysfunction and the evolution of the cancer genome. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background Telomere length has emerged as a prognostic marker in several cancers, including breast and chronic lymphocytic leukaemia (CLL). Telomere dysfunction has also been implicated in the formation of complex genome rearrangement patterns including chromothripsis, and in the progressive evolution of cancer genome architecture. This thesis explores the relationship between telomere length and genomic complexity across multiple cancer cohorts. Methods A novel software tool call teltool was developed that outperformed existing methods in predicting telomere length from Whole Genome Sequencing (WGS) data. Methods for assessing Structural Variants (SVs), Copy Number Alterations (CNAs) and genomic complexity in WGS data were developed, and applied to a breast cancer cohort (n=44), before expanding analysis to publicly available datasets of breast cancer (n=1591+80) and CLL (n=98). Results Across all cohorts, samples with shorter telomeres consistently exhibited increased genomic complexity. In breast cancer cohorts, the number of CNAs was increased (p < 0.05) when stratifying by measured and estimated telomere lengths. Similarly, in CLL, losses and total CNAs were higher (p < 0.05) in samples with shorter telomeres. All types of SVs showed increased frequencies (p < 0.05) in breast cancer cohorts with shorter telomeres, except for duplications in the ICGC cohort. Patterns of genome complexity were increased in shorttelomere groups with increased numbers chained SVs (p < 0.01) and complex joining profiles identified. Importantly, we observed a threshold effect where samples could be segregated into "short" and "long" telomere groups, associated with distinct levels of genomic complexity, and this phenomenon was most pronounced in cohorts with accurate telomere length measurements. The optimal threshold for partitioning was remarkably similar to the previously identified 'fusogenic' telomere length threshold that defined prognosis across several tumour types. Conclusion The findings of this thesis further establish the relationship between telomere length and cancer genome complexity. The results imply that telomere dysfunction plays a key role in generating large-scale genomic rearrangements and patterns of complexity. This work contributes to our understanding of the role of telomere dysfunction in cancer genomics and may have implications for diagnostics and prognosis.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	25 February 2025
Last Modified:	25 Feb 2025 11:37
URI:	https://orca.cardiff.ac.uk/id/eprint/176461

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