基因组关联研究已经鉴定出大约200个与乳腺癌风险相关的区段，但是这些区段的蛋白质靶标大多数仍未知。鉴定蛋白质靶标与生物标志物能够提高对癌症生物学与病因的理解，识别高风险人群进行癌症预防。在这项研究中，我们调查了在欧洲人群背景下，在乳腺癌协会联盟纳入的133,384名案例和113,789名对照组中，1142种循环蛋白质的遗传预测水平与乳腺癌风险之间的关系。我们发现了22种血液蛋白标志物与总体乳腺癌风险有关，其虚假发现率（FDR）小于0.05，其中有九种蛋白质是由位于先前报道的乳腺癌风险变异体至少500kb远的基因编码的。重点分析位于基因组关联研究鉴定的乳腺癌风险区段的124个编码基因，发现有20种蛋白质与总体乳腺癌风险有关，有一种蛋白质与三阴性乳腺癌风险有关，FDR小于0.05。调整基因组关联研究鉴定的风险变异体对这些蛋白质的关联进行了显著的衰减，提示这些蛋白质可能是这些基因组关联研究鉴定的风险区段的靶标。所鉴定蛋白质涉及多种生物过程，包括谷胱甘肽结合、STAT5信号和NF-κB信号通路。我们的研究为乳腺癌风险鉴定了新的蛋白质靶标和风险生物标志物。©2023 UICC.

Genome-wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high-risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1142 circulating proteins with breast cancer risk in 133 384 cases and 113 789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) <0.05, including nine proteins encoded by genes located at least 500 kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS-identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple-negative breast cancer risk at FDR <0.05. Adjustment for the GWAS-identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS-identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling and NF-κB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk.© 2023 UICC.