Exploring the cross-cancer effect of circulating proteins and discovering potential intervention targets for 13 site-specific cancers

Abstract

Background The proteome is an important 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 3991 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 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 Mendelian randomization 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 statistically significantly associated with 7 site-specific cancers. A total of 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, 5 of these identified proteins (CD86, CSF2RA, CXCL10, IL6R, and TAPBP) have been targeted for drug development in cancer therapy; 8 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 7 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.

Integrating plasma protein-centric multi-omics to identify potential therapeutic targets for pancreatic cancer

“…Given the above facts, it is worthwhile to give a deep insight into the causal relationship between plasma protein and PC to assist efficient identification of potential diagnostic markers and interference targets by applying advanced analytic methodology with high-support evidence and less likelihood for confounding bias. With the emergence of the MR method, one previous research preliminarily attempted the causal inference of plasma protein levels and pan-cancer, including PC [ 61 ]. Nevertheless, the instruments used in that study were not cis-acting, increasing the risk of horizontal pleiotropy.…”