Exploring the cross-cancer effect of circulating proteins and discovering potential intervention targets for 13 site-specific cancers
Jing Sun, Jia Luo, Fangyuan Jiang, Jianhui Zhao, Siyun Zhou, Lijuan Wang, Dongfeng Zhang, Yuan Ding, Xue Li- Cancer Research
- Oncology
Abstract
Background
The proteome is a significant reservoir of potential therapeutic targets for cancer. This study aimed to examine the causal associations between plasma proteins and cancer risk and to identify proteins with cross-cancer effects.
Methods
Genetic instruments for 3,991 plasma proteins were extracted from a large-scale proteomic study. Summary-level data of 13 site-specific cancers were derived from publicly available datasets. Proteome-wide Mendelian randomization (MR) and colocalization analyses were used to investigate the causal effect of circulating proteins on cancers. Protein-protein interactions and druggability assessment were conducted to prioritize potential therapeutic targets. Finally, systematical MR analysis between healthy lifestyle factors and cancer-related proteins was conducted to identify which proteins could act as interventional targets by lifestyle changes.
Results
Genetically determined circulating levels of 58 proteins were significantly associated with seven site-specific cancers. 39 proteins were prioritized by colocalization; of them, 11 proteins (ADPGK, CD86, CLSTN3, CSF2RA, CXCL10, GZMM, IL6R, NCR3, SIGLEC5, SIGLEC14, and TAPBP) were observed to have cross-cancer effects. Notably, five (CD86, CSF2RA, CXCL10, IL6R, and TAPBP) of these identified proteins have been targeted for drug development in cancer therapy; eight proteins (ADPGK, CD86, CXCL10, GZMM, IL6R, SIGLEC5, SIGLEC14, TAPBP) could be modulated by healthy lifestyles.
Conclusion
Our study identified 39 circulating protein biomarkers with convincing causal evidence for seven site-specific cancers, with 11 proteins demonstrating cross-cancer effects, and prioritized the proteins as potential intervention targets by either drugs or lifestyle changes, which provided new insights into the etiology, prevention, and treatment of cancers.