Using polygenic risk scores to refine risk and outcomes in high-grade serous ovarian cancer in Australia.

BACKGROUND: Ovarian cancer is characterised by high mortality and lacks effective screening, making prevention critical. Polygenic risk scores (PRS), which aggregate the effects of multiple common alleles, may capture a proportion of currently unexplained genetic risk. While PRS have been evaluated for risk prediction, their association with treatment response and survival remains unclear. This study assessed the utility of a PRS for predicting high-grade serous ovarian cancer (HGSOC) risk in an Australian population and its association with chemotherapy response and outcomes. METHODS: PRS were calculated for 1,097 HGSOC, and 812 controls using data from Australian research programs. Associations between PRS, OC risk, chemotherapy response, and survival were analysed. RESULTS: Each standard-deviation increase in PRS was associated with a 40% increase in HGSOC risk (OR 1.40, p < 0.001). Women in the top 1% of the PRS distribution had a lifetime OC risk approaching 3%. Higher PRS values showed a trend toward poorer outcomes, however these associations were not consistent across analyses. CONCLUSIONS: PRS were not clearly associated with chemotherapy response or survival but represent a significant risk factor for the development of HGSOC. Incorporating PRS into clinical models may improve risk stratification and support targeted prevention. IMPACT: As the first study to evaluate how PRS relate to both HGSOC risk and chemotherapy response and outcomes, we show that PRS are unlikely to serve as therapeutic biomarkers but support their use for enhanced risk-stratified prevention.