What question did this study set out to answer?

This research aims to identify molecular intermediates linking various risk factors to renal cell carcinoma (RCC).

April 5, 2026

Abstract 1481: Integrative analysis identifies potential proteomic intermediates associated with renal cell carcinoma and its risk factors

Key Points

This research aims to identify molecular intermediates linking various risk factors to renal cell carcinoma (RCC).
Investigated plasma proteins using a two-stage Mendelian randomization approach.
Stage 1 identified plasma proteins associated with 19 evaluated risk factors from UK Biobank data.
Stage 2 assessed the effects of these proteins on RCC using data from the largest RCC GWAS available.
Out of 2,940 plasma proteins, 2,339 were significantly associated with at least one of the risk factors.
Identified 33 proteins showing significant effects on RCC, with 28 mapping outside RCC GWAS loci.
Mediation analysis revealed that proteins like CDA and PILRB mediated a notable percentage of the effect of BMI on RCC.

Abstract

Abstract 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 (P1.7E-05) with at least one of the 19 RFs. Of these, 33 showed a significant effect on RCC (FDR5%) 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. Citation Format: Ibrahim Hossain Sajal, Andrew J. Song, Kevin M. Brown, Mitchell J. Machiela, Peter Kraft, Stephen J. Chanock, Mark P. Purdue, Diptavo Dutta. Integrative analysis identifies potential proteomic intermediates associated with renal cell carcinoma and its risk factors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1481.

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