Wang Qiankun, Wang Yi, Yin Tongxin, Feng Yuting, Ren Huihao, Xiao Xiao, Li Jiaoyuan, Cheng Liming
Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P. R. China.
Infect Agent Cancer. 2025 Sep 2;20(1):63. doi: 10.1186/s13027-025-00693-9.
Observational studies suggest a potential link between Hepatitis C virus (HCV) infection and extrahepatic cancers, but the causal relationship remains unclear.
We applied a two-sample Mendelian randomization (MR) approach to evaluate the causal relationships between HCV infection and various extrahepatic cancers. A two-step MR was used to identify potential mediators, followed by colocalization analysis to identify HCV-associated susceptibility genes (HSGs). A pan-cancer analysis using TCGA data was conducted, and a prognostic model based on HSGs was developed using least absolute shrinkage and selection operator (LASSO) regression and Cox models. Genetic risk score (GRS) analysis from the UK Biobank validated our findings.
We identified a causal link between genetic susceptibility to HCV infection and kidney cancer, both in univariable and multivariable MR analyses. The two-step MR identified five mediators in the causal pathway. IRF5 was highlighted as a key HSG in both the colocalization and pan-cancer analyses. Our prognostic model incorporating three HSGs predicted overall survival (OS) in kidney cancer patients. GRS analysis confirmed the association.
The present study provides evidence supporting a causal link between HCV infection and the development of kidney cancer.
观察性研究提示丙型肝炎病毒（HCV）感染与肝外癌症之间可能存在联系，但因果关系仍不明确。
我们应用两样本孟德尔随机化（MR）方法来评估HCV感染与各种肝外癌症之间的因果关系。采用两步MR来识别潜在的中介因素，随后进行共定位分析以识别HCV相关的易感基因（HSGs）。使用TCGA数据进行泛癌分析，并使用最小绝对收缩和选择算子（LASSO）回归及Cox模型建立基于HSGs的预后模型。来自英国生物银行的遗传风险评分（GRS）分析验证了我们的研究结果。
在单变量和多变量MR分析中，我们均发现HCV感染的遗传易感性与肾癌之间存在因果联系。两步MR在因果途径中识别出五个中介因素。在共定位和泛癌分析中，IRF5均被突出显示为关键的HSG。我们纳入三个HSG的预后模型可预测肾癌患者的总生存期（OS）。GRS分析证实了这种关联。
本研究提供了证据支持HCV感染与肾癌发生之间存在因果联系。
