Assessing the Causal Impact of the Circulating Proteome on Susceptibility to Gastrointestinal Cancer-Associated Characteristics
Authors: Lv Shiyao , Niu Lei , Fu Xiao-ming , Yao Gui-ming , Wen Qing , Fan Wen-you , Yang Bo 
Published: February 2025

ObjectivesThis research endeavors to pinpoint circulating proteins that exhibit a causal relationship with traits related to gastrointestinal cancer through a Mendelian randomization (MR) analytical framework. Dysfunctionof the human plasma proteome is frequently observed in a plethora of diseases, including gastrointestinal cancers. Owing to their pivotal role, circulating proteins present a compelling target for the development of therapeutic interventions aimed at gastrointestinal malignancies. However, the precise causal connections between these proteins and gastrointestinal cancer have yet to be elucidated. Mendelian randomization (MR), a well-established method in genetic epidemiology, enhances our ability to draw robust causal inferences regarding exposure‒outcomerelationships.
Methods A comprehensive large-scale two-sample Mendelian randomization (MR) approach was utilized to estimate the effects of thousands of plasma proteins on a spectrum of 12 gastrointestinal cancer-related traits. To ensure the robustness and validity of the MR findings, additional analyses were conducted, including Bayesian colocalization, Steiger filtering analysis, the evaluation of protein-altering variants, and the mapping of expression quantitative trait loci (eQTLs) to protein quantitative trait loci (pQTLs). These methodologies were employed to scrutinize the reliability of our causal inferences. Moreover, protein–protein interaction and pathway enrichment analyses were undertaken to increaseour understanding of potential therapeutic avenues, and drug targets were evaluated to identify promising candidates for gastrointestinal cancer treatment.
Through this meticulous MR-based analytical framework, we assessed the causal relationships between 2,518 distinct circulating proteins and the 12 gastrointestinal cancer- related traits. Our analysis successfully identified numerous proteins that are causally linked with gastrointestinal cancer, revealingboth previously recognized associations and novel findings. Additionally, in-depth protein–protein interaction and pathway enrichment analyses were performed on the MR-enriched proteins to further elucidate the pathogenesis of gastrointestinal cancer. These efforts also included an evaluation of drug targets, aiding in the prioritization of drug discovery efforts and the repurposing of existing pharmaceuticals for the treatment of gastrointestinal malignancies.
Results Numerous circulating proteins were identified as having putative causal effects on traits associated with gastrointestinal cancer. Remarkably, the majority of these proteins are either established as drug targets or are considered to possess druggable characteristics.
Conclusions Through the application of Mendelian randomization analysis, we identified a multitude of plasma proteins linked to traits associated with gastrointestinal cancer, illuminating protein-mediated mechanisms and identifying promising therapeutic targets for intervention. Our research provides a thorough examination of the causal relationships between circulating proteins and gastrointestinal cancer, encompassing thousands of plasma proteins and 12 cancer-related traits. This endeavor has yielded valuable insights into the underlying biological mechanisms and identified potential therapeutic targets, paving the way for novel treatment strategies against gastrointestinal cancer.