Genetics in the diagnosis and management of thyroid cancer

Background Thyroid cancer is the commonest endocrine malignancy, constituting around 1% of all cancers. Medullary thyroid carcinoma (MTC) is usually sporadic, but may occur in patients with germline mutations in the rearranged during transfection (RET) gene. The sporadic form lacks germline mutations but may harbour somatic RET mutations. The risk factors for differentiated thyroid carcinoma (DTC) are not well understood, and genetic predisposition accounts for a smaller proportion of DTC than MTC. Methods Presenting features of patients undergoing germline RET testing were analysed in order to explore the prevalence of germline RET mutations in patients with different clinical presentations in the UK population, and a systematic review of the literature was undertaken to investigate the clinical usefulness of somatic mutations in patients with sporadic MTC. Mendelian randomisation was utilised to investigate the causal roles of several proposed modifiable risk factors for thyroid cancer. Results By analysing results of 1,058 patients’ germline RET analysis, I found that 8.5% of patients with presumed sporadic MTC in fact have hereditary disease. The 3 systematic review on molecular genetics in sporadic MTC highlights the emerging role of somatic mutations and epigenetic markers in prognostication in sporadic MTC. Regarding risk factors for DTC, my Mendelian randomisation studies identified a causal association between lower thyroid stimulating hormone (TSH) levels and DTC, and a possible causal relationship between type 2 diabetes mellitus (T2DM) and DTC. I was however unable to provide any evidence using genetic epidemiological techniques for a causal role for obesity, smoking, alcohol consumption or physical exercise. Conclusions This thesis helps to illustrate patterns of clinical presentations of patients with germline RET mutations in the United Kingdom, and reports the novel use of mendelian randomisation to investigate the role of a range of lifestyle risk factors on the risk of thyroid cancer, raising some questions about the validity of previously reported observational findings, and paving the way for further research with the vital aim of understanding the modifiable risk factors for thyroid cancer.