Abstract 784: Proteome-wide mendelian randomization identifies causal association between plasma proteins and lung cancer

Abstract Background: Lung cancer is one of the world's main health issues, and the exploration of novel protein markers can help to understand the mechanisms of lung cancer development and the discovery of therapeutic targets. Based on this, we used proteome-wide Mendelian Randomization to determine causal associations between plasma protein levels and the risk of developing lung cancer and subtypes. Methods: We performed a two-sample Mendelian Randomization analysis using genome-wide association data for 4907 proteins from the deCODE genetics study and five lung cancer and its subtypes from the FinnGen database. Causal effects were estimated using the Wald-ratio method or the inverse variance weighted (IVW) method, with additional analyses using the other four common methods when the number of SNPs was more than one. The Steiger filter method was used to test the correct direction of the causal effect. Multiple corrections were utilized by the Benjamini-Hochberg method. Results: After filtering, we finally analyzed 4645 proteins for the causal association with lung cancer, and the F-statistic of the instrumental variable for each protein was more than 10. After multiple tests, the levels of four genetically predictive proteins were found to be associated with the risk of lung cancer, and one protein was associated with the risk of small-cell lung cancer. In detail, elevated levels of three genetically predicted proteins were significantly associated with increased risk of lung cancer, namely, SYSC (OR:4.75, 95%CI: 2.47-9.16, FDR=0.007), TM11D (OR: 1.34, 95%CI: 1.17-1.53, FDR=0.02), and PDC6I (OR: 2.35, 95%CI: 1.58-3.49, FDR=0.03). Elevated levels of FASLG (OR: 0.87, 95%CI: 0.82-0.92, FDR=0.007) were associated with a reduced risk of lung cancer. In addition, genetically predicted elevated levels of GRP (OR: 0.05, 95%CI: 0.01-0.17, FDR=0.02) were associated with an increased risk of small-cell lung cancer. The Steiger filter test showed that all directions were from proteins to lung cancer. Conclusion: In this study, we found that five proteins may have effects on the risk of lung cancer, in which genetically predicted SYSC, TM11D, and PDC6I were significantly associated with an increased risk of lung cancer, whereas FASLG and GRP were associated with a decreased risk of lung cancer and small-cell lung cancer, respectively. The above may help to explore the pathogenesis of lung cancer, but further comprehensive studies are still needed. Citation Format: Guojin Si, Wenxuan Li, Yacong Zhang, Zhangyan Lyu, Fengju Song, Kexin Chen. Proteome-wide mendelian randomization identifies causal association between plasma proteins and lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 784.