Therapeutic Targets for Gastric Cancer: Mendelian Randomization and Colocalization Analysis.

Abstract

Background: Gastric cancer (GC) is one of the most prevalent malignancies in the world. Most patients are diagnosed at advanced stages of the disease, primarily attributable to the insidious nature of early symptoms and the infrequent occurrence of routine screening. Further biomarkers are still needed for more comprehensive analysis, targeted prognostication, and effective treatment strategies. Plasma proteins are promising biomarkers and potential drug targets in GC. This study aims to identify potential therapeutic targets for GC by conducting a comprehensive proteome-wide Mendelian randomization (MR) and colocalization analyses.

Methods: Plasma proteins were obtained from the UK Biobank Pharma Proteomics Project (UKB-PPP), including Genome-Wide Association Study(GWAS)data of 1463 plasma proteins. Genetic associations with cancer were derived from the European Bioinformatics Institute (EBI) database, including 1029 patients and 475,087 controls (dataset: ebi-a-gcst90018849). MR analysis was conducted to assess the association between plasma proteins and the risk of developing cancer. Additionally, colocalization analysis was employed to investigate whether the identified proteins and gastric cancer exhibited shared incidental variants. Finally, using the extensive Finnish database in the R9 version, the potential harmful effects of target proteins on the treatment of gastric cancer were explored through the whole phenomenon association study (PheWAS).

Result: The results showed that 15 proteins may be associated with the risk of gastric cancer, and one protein is expected to become a therapeutic target for gastric cancer. There was a positive genetic association between plasma levels of 11 proteins and increased GC risk, while 4 proteins exhibited an inverse association with GC risk (P < 0.05). Colocalization analysis revealed that PPCDC and GC exhibited shared genetic loci among the 15 proteins examined, indicating that PPCDC may serve as potential direct target for intervention in GC. Further phenotype wide association studies showed that PPCDC (P < 0.05) could be associated with certain potential side effects.

Conclusion: Our research examined the causal relationship between plasma proteins and gastric cancer, shedding light on potential therapeutic targets. These findings have significant implications for the development of early diagnostic markers and targeted therapies for GC, potentially improving patient outcomes and survival rates. Future studies should validate these findings in diverse populations and explore the clinical applications of these targets.