Molecular characterisation of muscle-invasive bladder cancer
Thesis or Dissertation
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Background: Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease with a poor prognosis. There is a clinical need for biomarkers in MIBC to guide treatment strategy for individual patients and improve outcomes. In this work, I established a protocol to allow the collection of clinical material and data from patients with MIBC to support 3 pilot studies exploring potential clinically relevant biomarkers at a genomic and transcriptomic level. Method: In the first pilot study, plasma DNA was extracted from pre-treatment blood samples of 52 patients. In a subset of 10 patients receiving first-line chemotherapy, plasma DNA extracted from sequential samples underwent low-pass whole genome sequencing, with resultant copy number data being used to estimate tumour fraction. In the 2nd pilot, multiregion whole-exome sequencing was performed on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of 9 patients to identify potential aberrations to interrogate in plasma. In the 3rd pilot study, RNA extracted from FFPE tumour tissue of 43 patients treated with radical radiotherapy was profiled using the Nanostring platform. Non-negative matrix factorisation was applied to the gene expression data to explore molecular subtypes, with a focus on potential association with radiotherapy response. Results: Key findings include that baseline plasma DNA concentration is a prognostic factor for bladder cancer-specific survival. Plasma tumour fraction is correlated with radiological disease burden and may be an early indicator of response or resistance to chemotherapy. At a transcriptomic level, MIBC can be divided into 5 new molecular subtypes which appear to be associated with radiotherapy response. Conclusion: I have established a successful protocol to facilitate the collection of clinical material and data to support translational research in MIBC. Pilot studies have demonstrated the feasibility of applying a range of approaches and techniques to these samples, and my results have highlighted areas worthy of further investigation.
Bladder Neoplasms - Genetics
Clinical Academic Radiotherapy (Horwich)
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Institute of Cancer Research (University Of London)