A study of telomere biology in gliomas and drivers of genomic instability

Bhatt, Harsh 2025. A study of telomere biology in gliomas and drivers of genomic instability. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

This thesis investigates the nature of telomere-driven genome instability in adult diffuse gliomas. Telomeres in patients with GBM are shortened (median 4.0kb), compared to surrounding normal brain tissue (6.0kb) and non-matched epilepsy samples (6.9kb). In 146 patients with molecular GBMs, single telomere length analysis added significant prognostic utility to MGMT methylation status in predicting overall and progression-free survival. This was more evident when studying patients with complete resection at index surgery. Short telomeres had a differential impact on survival based on MGMT status, and further investigations underpinning the interplay between epigenetic regulation of DNA repair enzymes and telomere length are warranted. To assess the spectrum of genomic instability at single molecule level, telomere fusions were characterised through long-read nanopore sequencing. In 64 patients with GBM, 352 unique telomere fusions were individually characterised. 2/3rds were consistent with simple telomere:telomere end fusions, while ~1/3rd revealed a vast range of genomic complexity. Typical signatures included large subtelomeric deletions, junctional microhomology (~8- 10bp), and insertions from protein-coding oncogenes (CDK6 and ERG), common fragile sites, lncRNA, and telomeric as well as pericentromeric loci. Complex chromosomal rearrangements (CCR) with up to 17 insertions predominating from either the same genomic locus with frequent strand-switching at sites of potential hairpin structures or unique insertions spread across the genome with genes involved in supressing ultra-fine chromosome bridges between sister chromatids (FIGNL1) were seen. Such events are consistent with chromoanagenesis. Diffuse low grade gliomas also harboured telomere fusions, with distinct telomere profiles. ATRXMUT astrocytomas and ALT-positive GBMs both displayed significantly more telomeric and subtelomeric insertions in CCRs, consistent with a likely recombination based repair process. These findings suggest that telomere dysfunction is widespread amongst primary adult gliomas and promotes a spectrum of genome instability with unique substrates for DNA repair processes which have potential for therapeutic targeting and patient stratification.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	18 May 2026
Last Modified:	18 May 2026 14:21
URI:	https://orca.cardiff.ac.uk/id/eprint/187073

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