Integrative Genome-Wide Association Study with eQTL Combined with Transcriptome Analysis Reveals SLC18A1 as a Novel Biomarker for Small Cell Lung Cancer.

Abstract

Introduction: Small cell lung cancer (SCLC) is a malignant tumor with low differentiation, high recurrence, and poor prognosis. The importance of SCLC prevention is becoming increasingly apparent. The aim of this study was to identify novel biomarkers that could predict SCLC risk by analyzing genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL), along with transcriptomic data.

Methods: The summary of GWAS data on SCLC was obtained from the IEU Open GWAS Project database. eQTL data from 31,684 participants were acquired from the eQTLGen Consortium. Mendelian randomization (MR) was applied to identify potential causal or protective genes (CGs) for SCLC by integrating GWAS and eQTL data. Then, sensitivity analyses and heterogeneity tests were conducted. Meanwhile, transcriptome data on SCLC were analyzed to obtain differentially expressed genes (DEGs). Next, novel biomarkers of SCLC were obtained by intersecting CGs and DEGs. Moreover, novel biomarkers were subjected to functional enrichment analysis. Immunohistochemistry (IHC) was used to verify the expression of hub genes.

Results: Four novel biomarkers were identified based on GWAS, eQTL, and transcriptome data. We found that elevation of SLC18A1 could increase SCLC risk (OR=1.724; 95% CI: 1.070-2.778; P=0.025). In contrast, CD93 (OR=0.658; 95% CI: 0.444-0.975; P=0.037), TRPC6 (OR=0.346; 95% CI: 0.185-0.648; P<0.001) and SLA (OR=0.577; 95% CI: 0.362-0.921; P=0.021) might be associated with a reduced risk of SCLC. Moreover, SLC18A1 was expressed at higher levels, while CD93, TRPC6, and SLA were expressed at lower levels in SCLC compared to controls. IHC results showed that SLC18A1 was expressed at higher levels in SCLC patients (17/29, 58.6%) than in controls (7/29, 24.1%). KEGG analysis revealed that they were mainly enriched in the synaptic vesicle cycle and the cGMP-PKG signaling pathway.

Discussion: These findings provide genetic evidence linking SLC18A1, CD93, TRPC6 and SLA to SCLC risk. The identification of SLC18A1 as a causal gene and of CD93, TRPC6 and SLA as protective genes offers new biomarkers for early detection of SCLC. The consistency between genetic association and expression differences further supports their potential as reliable biomarkers for SCLC. Our study highlights possible targets for future prevention or therapy; however, additional functional experiments and larger validation cohorts are required.

Conclusion: The identified genes SLC18A1, CD93, TRPC6 and SLA are associated with SCLC risk, with SLC18A1 as a causal gene and the others as protective genes. They might serve as novel biomarkers for SCLC.