Exploration of potential novel drug targets and biomarkers for small cell lung cancer by plasma proteome screening

Background: Small cell lung cancer (SCLC) is characterized by extreme invasiveness and lethality. There have been very few developments in its diagnosis and treatment over the past decades. It is urgently needed to explore potential novel biomarkers and drug targets for SCLC. Methods: Two-sample Mendelian Randomization (MR) was performed to investigate causal associations between SCLC and plasma proteins using genome-wide association studies (GWAS) summary statistics of SCLC from Transdisciplinary Research Into Cancer of the Lung Consortium (nCase = 2,791 vs. nControl = 20,580), and was validated in another cohort (nCase = 2,664 vs. nControl = 21,444). 734 plasma proteins and their genetic instruments of cis-acting protein quantitative trait loci (pQTL) were used, whereas external plasma proteome data was retrieved from deCODE database. Bidirectional MR, Steiger filtering and phenotype scanning were applied to further verify the associations. Results: Seven significant (p < 6.81 × 10-5) plasma protein-SCLC pairs were identified by MR analysis, including ACP5 (OR = 0.76, 95% CI: 0.67-0.86), CPB2 (OR = 0.90, 95% CI: 0.86-0.95), GSTM3 (OR = 0.45, 95% CI: 0.33-0.63), SHMT1 (OR = 0.74, 95% CI: 0.64-0.86), CTSB (OR = 0.79, 95% CI: 0.71-0.88), NTNG1 (OR = 0.81, 95% CI: 0.74-0.90) and FAM171B (OR = 1.40, 95% CI: 1.21-1.62). The external validation confirmed that CPB2, GSTM3 and NTNG1 had protective effects against SCLC, while FAM171B increased SCLC risk. However, the reverse causality analysis revealed that SCLC caused significant changes in plasma levels of most of these proteins, including decreases of ACP5, CPB2, GSTM3 and NTNG1, and the increase of FAM171B. Conclusion: This integrative analysis firstly suggested the causal associations between SCLC and plasma proteins, and the identified several proteins may be promising novel drug targets or biomarkers for SCLC.