Yao Jiahui, Han Mingshuai
Department of Emergency Surgery, Linping Campus, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
Medicine (Baltimore). 2025 Jul 11;104(28):e43233. doi: 10.1097/MD.0000000000043233.
Previous research has highlighted the involvement of several human blood cells in skin cancer, but large-scale studies are lacking to explore their relationship and avoid confounding factors. Here, we comprehensively investigated the causal effect of blood cells on skin cancer subtypes across 4 different human microenvironments through 2-sample Mendelian randomization (MR) analysis and mediation analysis. Summary statistics of 91 human blood cells, 233 circulating metabolites, 731 immune cells, 46 antibody immune responses, 91 inflammatory cytokines, and 4 skin cancer traits (including cutaneous melanoma, nonmelanoma skin cancer, basal cell carcinoma, and squamous cell carcinoma) were derived from genome-wide association studies. The bidirectional 2-sample MR was used to determine the causality between exposures and outcomes. Additionally, comprehensive sensitivity analyses were performed to ensure the robustness of MR findings. Finally, the mediation analysis was applied to identify the role of blood cells in skin cancers mediated by 4 different microenvironments. MR revealed causal associations between 18 different types of human blood cells, 30 different types of circulating metabolites, 136 different types of immune cells, 17 different types of antibodies immune responses, 17 different types of inflammatory cytokines with skin cancers. Reverse MR analysis indicated skin cancers were causally associated with the levels of 4 different types of human blood cells. Mediation analysis revealed 19 mediation correlations during the causal effect from blood cells to skin cancers. Among them, 13 belonged to immune cells, 3 belonged to inflammatory cytokines, and 3 belonged to antibodies immune responses. Sensitivity analyses confirmed the consistency of these findings. This study represents the first comprehensive evaluation demonstrating causal relationships among human blood cells, circulating metabolites, immune cells, antibodies immune responses, inflammatory cytokines, and skin cancers, thereby providing novel insights and potential intervention targets for skin cancer treatment.
先前的研究强调了几种人体血细胞在皮肤癌中的作用，但缺乏大规模研究来探索它们之间的关系并避免混杂因素。在此，我们通过两样本孟德尔随机化（MR）分析和中介分析，全面研究了血细胞在4种不同人类微环境中对皮肤癌亚型的因果效应。91种人体血细胞、233种循环代谢物、731种免疫细胞、46种抗体免疫反应、91种炎性细胞因子和4种皮肤癌特征（包括皮肤黑色素瘤、非黑色素瘤皮肤癌、基底细胞癌和鳞状细胞癌）的汇总统计数据来自全基因组关联研究。双向两样本MR用于确定暴露与结局之间的因果关系。此外，还进行了全面的敏感性分析以确保MR结果的稳健性。最后，应用中介分析来确定血细胞在由4种不同微环境介导的皮肤癌中的作用。MR揭示了18种不同类型的人体血细胞、30种不同类型的循环代谢物、136种不同类型的免疫细胞、17种不同类型的抗体免疫反应、17种不同类型的炎性细胞因子与皮肤癌之间的因果关联。反向MR分析表明皮肤癌与4种不同类型的人体血细胞水平存在因果关联。中介分析揭示了从血细胞到皮肤癌的因果效应过程中有19种中介相关性。其中，13种属于免疫细胞，3种属于炎性细胞因子，3种属于抗体免疫反应。敏感性分析证实了这些结果的一致性。本研究首次进行了全面评估，证明了人体血细胞、循环代谢物、免疫细胞、抗体免疫反应炎性细胞因子与皮肤癌之间的因果关系，从而为皮肤癌治疗提供了新的见解和潜在的干预靶点。
