Usher, Inga Erica; (2023) Leveraging genomic technologies to understand the pathogenesis of chordoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chordomas are rare cancers comprising 4% of primary bone tumours and 20% of primary spinal tumours. They develop at the skull base and spine and are indolent but locally invasive by the time of presentation. Surgical resection is the only intervention that prolongs survival. However, the proximity of chordomas to critical structures often precludes complete excision, particularly at the skull base. Chordomas are resistant to conventional radiotherapy and chemotherapy, limiting options for management, and all treatments are associated with significant morbidity. Chordomas recur frequently and 40% of patients eventually develop metastases. Chordomas display notochordal differentiation and are linked to the notochord and their putative precursor, the Benign Notochordal Cell Tumour, by the expression of brachyury (TBXT). The pathogenesis of chordoma has not been fully elucidated. Most studies of the somatic landscape of chordoma have been small because of its rarity but these have generally revealed a quiet genome and half of cases lack a driver mutation. Yet clinical outcomes in patients with chordoma can vary widely around the median survival of seven years. There is a pressing need to identify molecular dependencies and predictors of clinical outcomes. Understanding the pathogenesis of chordoma, from the notochord to the Benign Notochordal Cell Tumour, will help inform efforts to address these needs. This project adds to the existing evidence that the Benign Notochordal Cell Tumour is the precursor of chordoma. Specifically, the findings implicate the rs2305089 single nucleotide polymorphism in TBXT in the pathogenesis of Benign Notochordal Cell Tumours; and a CRISPR-engineered induced pluripotent stem cell model adds weight to the role of this single nucleotide polymorphism in the development of notochordal tumours. Leveraging multi-omic technologies, with a focus on intratumour heterogeneity and the methylome, this project reveals that developmental pathways are active in chordomas but these are generally not driven by mutations. In contrast to most other cancers, genetic heterogeneity is rare within chordomas. Transcriptional heterogeneity was observed with regards to molecular targets and prognostic markers, however gene modules reflecting those seen in other cancer types were expressed and single-cell generated chordoma signatures were detected in a larger cohort of chordomas. Together these findings pave the way for uncovering non-genetic mechanisms of transcriptional regulation.

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