Integrative analysis identifies potential proteomic intermediates associated with renal cell carcinoma and its risk factors

Background: Renal cell carcinoma (RCC), the predominant form of kidney cancer, is influenced by several risk factors (RFs) including obesity, hypertension, and smoking. However, the molecular mechanisms linking these RFs to RCC remain unclear. Methods: We investigated plasma proteins (PP) as potential intermediates of markers of the effects of RFs on RCC using two-stage Mendelian randomization (TSMR) approach. In stage 1, we identified PPs associated with each of the 19 RFs evaluated (e.g., anthropometric traits, blood pressure, smoking behavior, blood cell counts, and kidney function), leveraging summary-level proteogenetic data on PPs from the UK Biobank Pharma Proteomics Project (N=34,557). In stage 2, we evaluated the effects of these RF-associated PPs on RCC, using the largest-to-date RCC GWAS (N = 864,690; cases=29,020). Results: Among 2,940 PPs, 2,339 were significantly associated (P<1.7E-05) with at least one of the 19 RFs. Of these, 33 showed a significant effect on RCC (FDR<5%) with 28 mapping outside RCC GWAS loci. Using multivariable MR, we estimated mediation effects of associated PPs, finding that proteins such as CDA and PILRB mediated up to 17.41% of BMI's effect on RCC, and APOL1 mediated 2.76% of white blood cell's effect. Convergent evidence from multiple in silico analyses with cis-MR, colocalization, and TCGA differential expression further prioritized TYMP, UMOD and USP28 as key protein intermediaries of the RF effects on RCC. TYMP and USP28, inversely associated with RCC risk, showed immune-related and tumor-suppressive effects, while UMOD was positively associated, potentially linking renal dysfunction to carcinogenesis. Functional annotation revealed enhancer activity and transcription factor (HIF) binding near these proteins. Conclusion: Our approach and results identify molecular intermediates that may link epidemiologic risk factors to RCC and highlight actionable candidates for laboratory investigation. Prioritized PPs associated to RCC and at least one RF, with results from multiple in-silico analyses Plasma-Protein Overall-MR cis-MR Colocalization Differential-Gene-Expression(TCGA) Nearest-GWAS-Signal* Name Region Beta P-value Beta P-value FoldChange P-value(FDR) RSID P-value TYMP 22q13.33 -0.17 2.6E-06 -0.29 4.9E-08 9.95E-01 6.81 1.7E-14 rs131813 5.4E-09 UMOD 16p12.3 0.05 1.4E-06 0.06 1.3E-08 8.93E-01 0.00 5.1E-15 rs7203642 8.2E-06 USP28 11q23.2 -0.31 4.5E-05 -0.46 4.1E-05 9.98E-01 0.85 5.0E-05 rs4288784 1.2E-05 * Strongest GWAS association within +/- 1Mb of the transcription start site of the protein