Exploring potential causal effects of circulating inflammatory proteins on hematologic malignancies and identifying cross-cancer drug targets: a Mendelian randomization study.

Abstract

Background: Although a substantial body of research has underscored the pivotal role of inflammatory proteins in hematologic malignancies, precise understanding of the underlying mechanisms is limited. Therefore, it's necessary to explore the possible causal relationships between specific circulating inflammatory proteins and these malignancies by using a genome-wide association approach.

Methods: To evaluate the possible causal effects, we performed a two-sample Mendelian randomization (MR) study. Summary statistics for 91 proteins, sourced from large-scale genome-wide association studies, were integrated with data on 11 hematologic malignancies from the FinnGen consortium. Inverse variance weighting was applied as the primary method for MR analysis, with detailed sensitivity analyses conducted to ensure robustness. Furthermore, protein-protein interaction analysis and cross-cancer effect assessments were performed to identify potential common drug targets.

Results: Our analysis demonstrated both positive and negative associations of circulating inflammatory proteins on the development of 11 hematologic malignancies. Nine proteins exhibited cross-cancer effects. MCP-1, CXCL8, IL-1α, and SCF were associated with an increased risk of hematologic malignancies, while IFN-γ, IL-10, CD40, SULT1A1, and CXCL5 were associated with a reduced risk.

Conclusions: The results of the study provided possible causal evidence for the involvement of circulating inflammatory proteins in the pathogenesis of eleven hematologic malignancies. Nine proteins with cross-cancer effects were of special interest, and their potential as targets in the therapeutic intervention of blood malignancies was highlighted.