Proteome-wide Mendelian randomization and colocalization analysis uncovers druggable targets for lung cancer across multiple phenotypes and complications.

[BACKGROUND] Lung cancer remains a leading cause of cancer-related mortality, necessitating novel therapeutic targets. The plasma proteome represents a key source for such targets.

[METHODS] Proteome-wide Mendelian randomization (MR) and colocalization analyses were conducted to assess the causal effects of plasma proteins on lung cancer subtypes and complications. Genetic instruments (cis-pQTLs) for 2,090 proteins were derived from plasma proteome data (54,306 UK Biobank and 35,559 Icelandic participants). Lung cancer phenotype data were obtained from FinnGen R10.

[RESULTS] MR identified seven plasma proteins showing significant causal associations with specific lung cancer phenotypes: high GGT1 increased non-small cell lung cancer (NSCLC) risk (OR 1.27, 95% CI 1.10-1.46; P = 0.0261), GFRA2 increased the SCLC risk (OR 1.65, 95% CI 1.24-2.21; P = 0.0462), and higher advanced glycosylation end-product specific receptor reduced the squamous cell carcinoma risk (OR 0.338 per SD increase, 95% CI 0.209-0.548; P = 0.0138). Fifteen proteins showed associations with lung cancer complications. Colocalization strongly supported causal roles for eight proteins: FKBP1B (OR 1.15, 95% CI 1.09-1.22; P = 0.00264), F11(OR 1.01, 95% CI 1.01-1.01; P = 1.47 × 10), ABO (OR 1.11, 95% CI 1.06-1.21; P = 5.82 × 10), F2 (OR 3.04, 95% CI 1.74-5.31; P = 0.0102), and VSIG10L (OR 1.006, 95% CI 1.00-1.01; P = 0.0159).

[CONCLUSION] This study reveals causal proteins for various lung cancer phenotypes and complications, emphasizing causal pathways and potential therapeutic targets for lung cancer and providing new insights into its etiology, prevention, treatment, and therapy.