Plasma Proteome Profiling Identifies Biomarkers and Potential Drug Targets for Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC), as one of the most commonly diagnosed cancers globally, requires expedited identification of new drug targets. We conducted proteome-wide MR using genetic data for 4,853 plasma proteins. Summary-level data on lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) were extracted from GWAS meta-analyses (11,273 and 7,426 cases, respectively) and FinnGen cohort (1,590 and 1,510 cases, respectively). We genetically identified eight proteins with a causal role in the etiology of NSCLC. Lower levels of five proteins (CDH17, CXADR, FAM3D, POGLUT3, SFTPB) and higher levels of two proteins (CEACAM5, KLK1) were linked to increased LUAD risk, while higher CD14 levels were associated with elevated LUSC risk. Two proteins, POGLUT3 and SFTPB were validated through Bayesian colocalization. One protein SFTPB was identified using SMR and HEIDI tests. Bidirectional MR found no reverse causality. The primary findings were validated through scRNA-seq, GeneMANIA, GO analysis, druggability assessments and PheWAS analysis. These protein-coding genes are primarily expressed in epithelial cells, macrophages, monocytes, and endothelial cells. Furthermore, CEACAM5, KLK1, and CD14 correspond to existing drugs. These proteins may deepen our comprehension of the etiology and could serve as appealing novel biomarkers and drug targets for NSCLC management.