Clinical and molecular aspects of adrenal tumourigenesis

Abstract

The aims of this thesis were to examine the clinical and molecular aspects of benign and malignant adrenocortical tumours. Initial research focused on correlating KCNJ5 genotype-phenotype correlations in primary aldosteronism. It was noted that 41% patients were found to have somatic mutations in KCNJ5, G151R and L168R. Mutation carriers were predominately female and significantly younger at presentation and were more likely to be cured following surgery. Further work focussed on malignant adrenocortical carcinoma (ACC). Analysis in a cohort of patients showed that advanced age, advanced disease and the lack of preoperative endocrine investigations were poor prognostic factors. There was also a trend for improved resection margins and recurrence-free survival in patients undergoing surgery with higher-volume surgeons, suggesting that management in experienced units may result in improved outcomes. Tissue microarray technology was utilised in order to identify novel protein signatures that would be able to predict clinical outcomes in patients with ACC. A panel of previously overexpressed genes were validated at the tissue level. A novel combination of predictive and prognostic biomarkers was revealed, with over-expression of Ki-67, TOP2A and EZH2 being associated with poorer outcomes whereas over-expression of BARD1 was associated with improved outcomes. The role of microRNA-129 (miR-129) was explored in ACC tumour biology utilising an ACC cell line, a miRNA known to be under-expressed in adrenocortical tumours. It was found that restoration of miR-129 resulted in cell-cycle arrest, heralding a possible tumour-suppressor role for miR-129. Further investigations demonstrated that SOX4 was a potential downstream target of miR-129, the two having been previously described in other malignancies but not in ACC. The findings in this thesis have provided significant contributions to the understanding of both benign and malignant adrenocortical tumours. However, much work is still needed to refine our understanding of adrenal disease and the findings from this body of work provide the basis for ongoing studies.