Abstract:
Granulosa cell tumours (GCTs) of the ovary represent a specific subset of malignant ovarian tumours and account for only 2% of all ovarian cancers. Despite having a better short term prognosis than the more common epithelial cancers, approximately 80% of patients with advanced or recurrent tumours die from their disease. Consequently better therapeutic targets and biomarkers are needed if outcomes of GCT patients are to improve. In contrast to the hypothesis-driven, reductionist approach of previous studies, the fundamental aim of this thesis was to adopt a hypothesis-generating, unbiased approach utilising high-throughput genomic technologies including gene expression microarrays and Next-Generation Sequencing, in order to develop a more comprehensive understanding of the molecular changes that are involved in ovarian GCTs. Aside from the characteristic FOXL2 mutation identified in adult-subtype tumours, a systematic DNA mutation screen of known cancer genes revealed that known oncogenes and tumour suppressor genes are not common drivers of ovarian GCTs. In addition, results from transcriptome analysis suggested agents targeting angiogenesis and tyrosine kinase receptors may be effective in treatment of GCTs. Furthermore, analysis of miRNA expression profiles revealed expression signatures unique to the two GCT subtypes, and also identified microRNA-184 to be a novel biomarker of disease recurrence for the adult-subtype. With a focus on oestrogen receptor beta (ERβ) signalling that has previously been demonstrated to be important in GCTs, this study also investigated its role using the gene expression profiles of both in vivo GCT tumours and in vitro GCT cell lines. In addition to regulating the cell cycle, extracellular matrix organisation and integrin signalling, ERβ target genes were found to be enriched for binding sites for other transcription factors such as nuclear factor-kappa B and beta-catenin, suggesting that non-classical ERE mode of signalling is perhaps the main mechanism of ERβ function in ovarian GCTs. The work in this thesis furthers our understanding of the molecular changes at multiple levels (DNA mutation, expression changes in mRNA and miRNA expression) that contribute to the pathogenesis ovarian GCTs, helping to highlight suitable targets that can be targeted for therapy or developed into novel prognostic and/or predictive markers in the future.