Circulating tumour DNA in advanced thyroid cancer
Thesis or Dissertation
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Conventional biomarkers currently used in thyroid cancer are not disease specific and fluctuate in advanced disease, making interpretation difficult. Circulating tumour DNA (ctDNA) has been shown to be a useful in other solid tumours. The main objective of this thesis was to ascertain if ctDNA has potential as a novel biomarker in thyroid cancer. This was undertaken through examining the hypothesis that ctDNA is detectable in the plasma of patients with advanced thyroid cancer. In support of this, and to help with future studies, two further hypotheses were examined: that a thyroid-specific targeted gene panel would offer superiority over a currently used generic panel, and that resistance to targeted therapy in thyroid cancer is due to a genetic variant detectable in ctDNA. Through multi-mutational analysis of plasma, ctDNA was detected in the majority of patients with advanced thyroid cancer. ctDNA measurement may offer superiority over conventional markers in several scenarios: earlier detection of progression in medullary thyroid cancer; as an alternative biomarker when conventional markers are not available; more rapid assessment of the disease status in response to targeted therapies, thereby potentially allowing prompter discontinuation of futile therapies. A novel thyroid-specific targeted gene panel was designed and validated successfully. This performed favourably compared to a generic panel, with lower costs, faster workflow and greater detection rate. Therefore, it will be used in future studies. Lastly, whole exome sequencing of plasma samples taken from patients with advanced thyroid cancer pre- and post-resistance to targeted therapies may be a useful technique for discovering genomic mechanisms of resistance. Several leads were generated for putative resistance-conferring variants, and areas in the workflow were identified that could be improved to allow for more successful future studies. These early results support the hypothesis that ctDNA may be a clinically useful biomarker in thyroid cancer. Clinical vailidity and utility will need to be confirmed in further large prospective trials.
Thyroid Cancer - Molecular Biology
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Institute of Cancer Research (University Of London)