Biochemistry and Pharmacology - Theses
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ItemIntegrated analysis of distinct molecular profiles of ovarian cancer( 2013)Epithelial ovarian cancer is the fifth most common cancer among women and causes more deaths than any other female reproductive cancer. However, it is a general term for a series of molecularly, histologically and aetiologically distinct diseases. From a clinical perspective, two of the most difficult to manage subtypes are high-grade serous cancer (HGSC) and ovarian clear cell carcinoma (OCCA). HGSC is the most common form of epithelial ovarian cancer and accounts for more than 60% of death due to ovarian cancer. Though more than 70% of HGSC patients respond to primary therapy, the majority of these patients experience recurrence of treatment-resistant disease. OCCA on the other hand is relatively infrequent but is often resistant to even primary therapy. This thesis investigates the molecular changes associated with HGSC and OCCA with an aim of identifying therapeutic targets or novel biomarkers. In the first part of this thesis, I investigate the HGSC genome structure using genome-wide copy number profiles of well-annotated HGSC samples obtained from several research projects, including The Cancer Genome Atlas (TCGA) and the Australian Ovarian Cancer Study (AOCS). Systematic analysis of high quality copy number profiles identified several regions recurrently altered in HGSC genomes. Using a novel statistical method, I found associations between regions of alterations. The TCGA data portal provided both copy number and gene expression profiles of samples and I made use of this dataset to estimate the relationship between genomic copy number and gene expression levels. Finally I found several novel ovarian cancer genes by combining gene expression, genomic copy number and clinical outcome data. In the next part of my thesis I investigate the signalling pathways disrupted in HGSC. Prior to the start of my PhD, our laboratory had established the presence of molecular subtypes of HGSC. I investigated the molecular changes within a homogenous subtype and identified a specific signalling pathway disrupted in the C5 molecular subtype. The BRCA genes play a central role in the pathogenesis of HGSC. Therefore I investigated the molecular changes associated with BRCA1 and BRCA2 mutant tumours compared with their wild type counterparts. I show that the BRCA1 mutant tumours are associated with a specific molecular subtype of HGSC and provide a gene expression signature that can identify BRCA1 mutant tumours. In the final part of my thesis I investigate the molecular profiles of OCCA. Systematic analysis of gene expression and genomic copy number changes led to the identification of serum levels of IL6 as a potentially independent prognostic marker. These analyses also led to the identification of a molecular target, MET, that may be therapeutically targeted in OCCA. This thesis is centred on the question of identifying the biologically and clinically relevant molecular changes associated with two aggressive histological subtypes of ovarian cancer. I have used principled bioinformatic analysis of gene expression, genomic copy number and clinical outcome data of large cohorts obtained from existing genomic data to achieve this aim.