David Stacey

Protein markers of ovarian cancer and its subtypes: insights from proteome-wide Mendelian randomisation analysis

Abstract Background Ovarian cancer (OC) is often diagnosed at an advanced stage when prognosis is poor. We aimed to identify blood plasma proteins predictive of OC risk. Methods We conducted proteome-wide Mendelian randomisation (MR) analyses using summary-level protein quantitative trait locus data covering 2337 plasma proteins, and genome-wide association data on OC and its subtypes (up to 25,509 cases) from the Ovarian Cancer Association Consortium. Wald ratio or inverse-variance weighted MR analysis was used as the primary method, depending on the number of instruments. We evaluated pleiotropy using MR-Egger intercept test and leave-one-out analysis. Results From 2337 plasma proteins, 12 were associated (p < 7.4 × 10−5) with OC or its subtypes. Robust evidence linked follitropin subunit beta (FSHB) with endometrioid OC (per SD higher, OR 2.41, 95% CI 1.56, 3.71). Associations for the other 11 proteins could be explained by pleiotropy from ABO or MAPT-AS1 loci. We identified 12 suggestive associations with OC or its subtypes at nominal threshold (p < 0.05), involving 11 plasma proteins, with no evidence of pleiotropy from leave-one-out and MR-Egger intercept tests (P intercept > 0.17). Potential drug targets were identified for follitropin receptor and eight other proteins. Conclusion Our study suggests FSHB and 11 additional plasma proteins as of potential interest in OC (or subtypes) prognosis, mostly representing potentially druggable targets.