Appraising the causal role of cathepsins in genitourinary carcinoma: a two-sample mendelian randomization and prospective study based on 36,225 individuals

Background
Cathepsin family proteases play an important role in the carcinogenesis of genitourinary carcinomas. However, the causality between serum cathepsin levels and genitourinary carcinomas remains uninvestigated.

Methods
In this study, we conducted a two-sample Mendelian Randomization (MR) analysis exploring the causal association between different types of cathepsins and genitourinary carcinomas. Univariate, bidirectional and multivariate MR analyses were conducted based on the genome-wide association studies. Moreover, linkage disequilibrium score regression (LDSC) analysis, colocalization and transcriptomic analysis were also performed. 36,225 Individual data from UK biobank was utilized for further validation.

Results
Our findings revealed seven causal associations following univariate analysis, in which five correlations were further validated in multivariate analysis. Cathepsin S (CTSS) was positively associated with papillary renal cell carcinoma (pRCC) [IVW: OR (95%CI) 1.444 (1.103–1.890), p: 8*10–3], and LDSC analysis indicated a genetic correlation between CTSS and pRCC [rg (SE): 0.559 (0.225); p: 0.013]. Other causal correlations included cathepsin B (CTSB), positively associated with testicular non-seminoma, and cathepsin L2 (CTSL2/CTSV), negatively associated with overall kidney cancer and pRCC. Transcriptomic analysis further validated the findings from MR analysis. In the UK biobank, CTSL2 was found to be negatively associated with the risk of cancer of the kidney [HR (95%CI) 0.567 (0.368, 0.873), p: 0.01].

Conclusions
Cathepsins played an important role in urogenital carcinogenesis. Further large-scale studies are warranted for extended validation.