Proteome-wide Mendelian randomization and single-cell sequencing analysis identify the association between plasma proteins and gastric cancer.

Abstract

Targeted therapy is a crucial treatment modality for advanced gastric cancer, with several targets already identified, and the exploration of new targets is important. In this study, our aim was to identify plasma proteins causally associated with gastric cancer to explore novel genetic targets for the disease. Firstly, we utilized protein quantitative trait loci data for 4,907 plasma proteins and genome-wide association study data for gastric cancer to conduct Mendelian randomization (MR) analyses. This was followed by summary-data-based MR analysis on the identified plasma proteins. We then analyzed single-cell sequencing data from the Gene Expression Omnibus database to describe the distribution of genes corresponding to these proteins across different stages and cell types of gastric cancer. MR analysis identified 12 plasma proteins with potential causal associations with gastric cancer, among which motilin (MLN) and THSD1 passed the summary-data-based MR test. These proteins showed no evidence of pleiotropy nor heterogeneity. In single-cell sequencing analysis, EPHB4, KDR, SEMA6B, CDH1, and C1GALT1C1 were found to be enriched in specific cell types within gastric cancer. KDR and LIFR exhibited significant differential expression between gastric cancer and normal tissues. All the 12 genes displayed differential expression across different stages of gastric cancer. Overall, our study identified several plasma proteins with potential causal relationships to gastric cancer. This provides potential candidate targets for gastric cancer research and advances our understanding of the disease's genetic foundations.