卵巢癌及其亚型的蛋白质标志物：全蛋白质组孟德尔随机化分析的见解

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

作者信息

Mulugeta Anwar, Stacey David, Lumsden Amanda L, Madakkatel Iqbal, Lee S Hong, Mäenpää Johanna, Oehler Martin K, Hyppönen Elina

机构信息

Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia.

South Australian Health and Medical Research Institute, Adelaide, SA, Australia.

出版信息

Br J Cancer. 2025 Aug 28. doi: 10.1038/s41416-025-03143-w.

DOI:10.1038/s41416-025-03143-w

PMID:40877637

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) 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 > 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.

摘要

背景

卵巢癌（OC）通常在预后较差的晚期被诊断出来。我们旨在确定可预测OC风险的血浆蛋白。

方法

我们使用涵盖2337种血浆蛋白的汇总水平蛋白质定量性状位点数据，以及来自卵巢癌协会联盟的OC及其亚型（多达25509例）的全基因组关联数据，进行了全蛋白质组孟德尔随机化（MR）分析。根据工具数量，将 Wald 比率或逆方差加权 MR 分析用作主要方法。我们使用 MR-Egger 截距检验和留一法分析评估多效性。

结果

在2337种血浆蛋白中，有12种与OC或其亚型相关（p < 7.4×10）。有力证据表明促卵泡激素β亚基（FSHB）与子宫内膜样OC相关（每标准差增加，OR 2.41，95%CI 1.56，3.71）。其他11种蛋白质的关联可以由ABO或MAPT-AS1基因座的多效性来解释。我们在名义阈值（p < 0.05）下确定了12种与OC或其亚型的提示性关联，涉及11种血浆蛋白，留一法和MR-Egger截距检验均未发现多效性证据（P > 0.17）。确定了促卵泡激素受体和其他8种蛋白质的潜在药物靶点。