Integrative analysis prioritizes proteins 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, including obesity, hypertension, and smoking. The molecular mechanisms linking these risk factors to RCC, however, remain unclear.

METHODS

We investigated plasma proteins as potential intermediates of the effects of risk factors on RCC using 2-step mendelian randomization. In step 1, we identified plasma proteins influenced by each risk factor, using genome-wide association study summary statistics from the UK Biobank Proteomics (n = 34 557) for plasma proteins and 19 risk factors encompassing anthropometric traits, blood pressure, smoking behavior, blood cell counts, and kidney function. In step 2, we evaluated the effects of these risk factor-associated plasma proteins on RCC, using the largest-to-date RCC genome-wide association study (29 020 cases). Proteins strongly associated both with risk factors and with RCC were further prioritized through convergent evidence from multiple downstream analyses.

RESULTS

Among 2940 plasma proteins, 2339 were statistically significantly associated (P < 1.7×10-05) with at least 1 of the 19 risk factors. Of these 2339 proteins, 33 showed a statistically significant effect on RCC (false discovery rate < 5%), with 28 mapping outside RCC genome-wide association study loci. Using multivariable mendelian randomized, we estimated the mediation effects of associated plasma proteins, finding that proteins such as APOL1 mediated 2.76% of white blood cells' effect. Convergent evidence from multiple downstream analyses prioritized TYMP, UMOD, and USP28 as key protein intermediaries of the risk factor effects on RCC. TYMP and USP28, both inversely associated with RCC risk, showed immune-related and tumor-suppressive effects, while UMOD was positively associated, potentially linking kidney biomarkers to carcinogenesis.

CONCLUSIONS

Our analysis highlights plasma proteins as intermediates of the effect of distinct risk factors on RCC, thereby nominating molecular targets for further investigation.