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Title: Investigating the impact of molecular stratification on ovarian cancer treatment and outcome
Author: Hollis, Robert Leonard
ISNI:       0000 0004 7969 1819
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Ovarian cancer is the most lethal gynaecological malignancy in the developed world. High grade serous (HGS) ovarian carcinoma (OC) represents the majority of cases and most frequently presents at advanced stage, where the five year survival rate is around 30%. Over the last two decades, our understanding of the molecular events underpinning HGS OC has advanced substantially, identifying cases rendered deficient in homologous recombination DNA repair (HR) by virtue of BRCA1 or BRCA2 (BRCA) mutation (BRCAm). BRCAm patients experience a distinct clinical phenotype which has been translated into stratification of routine OC care, with poly-(ADP-ribose) polymerase (PARP) inhibitors showing marked efficacy in this patient group. However, phenotypic characterisation of HGS OCs in non-BRCA molecular subtypes is less well defined and ultimately molecular characterisation of OC beyond BRCAm is not used to guide disease management or prognostication. This body of work performs characterisation of clinical specimens from patients diagnosed with OC, identified retrospectively using the Edinburgh Ovarian Cancer Database, through which detailed patient outcome data is available. These analyses aim to determine the clinical consequences of molecular events that underpin OC, correlating specific events with survival and chemotherapy response. Firstly, a cohort of OC treated with pegylated liposomal doxorubicin (PLD) is identified and characterised using next generation sequencing (NGS) analysis for the BRCA genes to determine whether BRCAm patients are more sensitive to this non-platinum DNA damaging agent. HGS OCs with BRCA sequence aberrations demonstrated significantly higher response rates to PLD, including a higher response rate in patients harbouring the BRCA1 SNP rs1799950. vii Pre-existing gene expression data for a cohort of 265 HGS OC patients is then used to identifying a subgroup of patients who have high expression of C11orf30/EMSY, whose gene product encodes a BRCA2-binding protein reported to disrupt BRCA2 function. These patients are demonstrated to behave similarly to BRCAm patients, showing prolonged survival and hypersensitivity to platinum-based chemotherapy. The survival benefit of high- EMSY HGS OC patients is recapitulated in multiple independent datasets, including the MRC ICON7 clinical trial cohort. Finally, integrated molecular characterisation of a large HGS OC cohort is performed to investigate the overlap and interplay between genomically and transcriptomically-defined subgroups described in HGS OC. Tumour-infiltrating lymphocytes are quantified and overlaid with molecular data to deconvolute the clinical impact of molecular subtypes with high granularity. These analyses reveal differential distribution of genomic subgroups between transcriptionally-defined subtypes, and identify the Angio subtype as a subtype demonstrating poor tumour engagement by the immune system. Patients with HGS OC harbouring CCNE1 copy number gain are demonstrated to display poorer outcome. Integrated molecular subtyping separates HGS OCs into three classes each with distinct OS profiles, and reveals potential novel context-specific associations of molecular events with clinical outcome. Together, these data extend our knowledge of the clinical impact of molecular subtypes of HGS OC, paving the way for improved stratification of OC patient management.
Supervisor: Gourley, Charlie ; Sims, Andrew ; Herrington, Simon Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: ovarian cancer ; BRCA gene ; EMSY ; Edinburgh Ovarian Cancer Database ; chemotherapy response ; pegylated liposomal doxorubicin ; HGS