Abstract
Cysteine cathepsins are a family of lysosomal proteases that are often overexpressed in several human malignancies and haves been linked to cellular genomic alterations, disturbances in genomic stability, and the onset and spread of cancer. Recent studies have shown alterations in cysteine cathepsins in malignant ovarian tumors. However, it remains unclear whether there is a causal relationship between ovarian cancer, and its subtypes, and the cathepsin family. This study utilized two-sample Mendelian randomization (MR) analysis to examine this potential causal relationship. Genetic instruments derived from publicly available genetic summary data were used for the analyses. For MR analysis, the inverse-variance weighted method, weighted median method, and MR-Egger regression were employed. Multivariate MR analysis was performed concurrently. Univariate MR analysis indicated a strong correlation between decreased incidence of low-grade serous ovarian cancer and elevated levels of cathepsin L2 (odds ratio = 0.803, 95% confidence interval = 0.685-0.942, P = .007), whereas clear cell ovarian cancer showed a strong correlation with elevated levels of cathepsin H (odds ratio = 1.149, 95% confidence interval = 1.036-1.274, P = .008). Multivariate analysis, adjusted for 9 different cathepsins as covariates, confirmed the genetic relationships between cathepsin L2 and low-grade serous ovarian cancer and between cathepsin H and clear cell ovarian cancer. Our results suggest a causal relationship between cathepsins and ovarian malignancy and its subtypes. Cathepsin L2 has a protective effect on low-grade serous ovarian cancer, whereas cathepsin H is an adverse risk factor for clear cell ovarian cancer.