Epithelial ovarian cancer is a poor-prognosis malignancy. While patients are commonly initially sensitive to chemotherapy, most patients eventually relapse with drug resistant disease and overall survival rates are low. We are now beginning to understand that ovarian cancer is a heterogeneous disease by several criteria, and that mechanisms of chemo-resistance differ from patient to patient. Improvements in outcome are likely to require individualization of treatment rather than the current ‘one-size-fits-all’ approach. We have undertaken a series of genetic and genomic studies to examine alterations that contribute to treatment response and whole genome sequence analysis to survey structural variation at high resolution.

The majority of serous ovarian carcinomas are considered to be high-grade by histological criteria and have TP53 driver mutations. Just over 50% of this sub-type have defects in BRCA-related homologous recombination DNA repair pathways, which contribute to improved chemo-response and patient survival. However, reversion events and loss of BRCA1 promoter methylation can lead to acquired chemotherapy resistance. Low-grade serous ovarian cancer (LGSC) is a completely different entity, from a molecular perspective. LGSC are TP53 wild-type and are intrinsically resistant to platinum-based chemotherapy. Mutations in the Ras pathway are found in ~50% of LGSC and new, targeted agents are being tested in clinical trials. However, trials in LGSC are challenging as it is relatively rare, and the subtype is not completely defined at a molecular level.

Collectively our findings underscore the complexity of the ovarian cancer genome. Understanding the molecular drivers and mechanisms of treatment response is an important step forward in improving clinical outcomes through individualization of cancer care.