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Investigating the impact of telomere dysfunction on the chronic lymphocytic leukaemia genome

Escudero-Monreal, Laura 2017. Investigating the impact of telomere dysfunction on the chronic lymphocytic leukaemia genome. PhD Thesis, Cardiff University.
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Abstract

Short dysfunctional telomeres can result in chromosome fusions that drive genomic rearrangements and ultimately malignant progression. In Chronic Lymphocytic Leukaemia (CLL), telomere length (TL) is a powerful predictor of patient survival. The aim of this project is to understand the role that telomere dysfunction plays in driving the evolution of the CLL genome. Telomere fusions were detected in 71% of 276 CLL patients with short telomeres (TL<3.81Kb). From 9 CLL patient samples with the highest fusion frequency (>4.20x10-5/diploid genome), 914 telomere fusions were characterised using Illumina HiSeq paired-end sequencing. In addition to intra- and inter-chromosomal recombinations, telomere fusions with non-telomeric loci were detected, including the ancestral telomere at Chr2q13, mitochondrial DNA, and loci associated with copy number aberrations in CLL. Telomere fusions also incorporated genes expressed in CLL-B lymphocytes and other oncogenes, suggesting that active chromatin is more prone to damage and aberrant repair. These events were potentially mediated by A-NHEJ that requires microhomology. Translocations involving hTERT, proximal to the 5p telomere, have previously been detected in CLL and associated with telomerase upregulation. In this study, 5p telomere fusions were identified in 22.6% patient samples and 172 fusion events that involved 5p were characterised, which may explain mechanisms of telomerase reactivation in cancer. Surprisingly, 67% of the 9 patients presented bimodal TL distributions compared to the overall cohort (4% of 276), consistent with intra-tumour heterogeneity, which was confirmed for one patient. For this patient with indolent disease, chromosomal rearrangements were detected, in addition to a novel mutation in REV3L implicated in translesion synthesis that may negatively impact cancer cells fitness and be a potential therapeutic target. This study shows that telomere dysfunction in CLL initiates genome-wide instability providing a source for genetic variability that allows intra-tumour heterogeneity and tumour progression. However, therapeutically-exploiting this instability could prove beneficial for patient outcome.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 12 February 2018
Last Modified: 12 Feb 2018 11:11
URI: http://orca.cf.ac.uk/id/eprint/108961

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