Liu Wenbo, Wang Zhiyuan, Yang Zhiran, Huo Bingjie, Song Yanru, Li Yong, Tan Bibo
The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China.
Department of Traditional Chinese Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China.
Heliyon. 2024 Sep 27;10(19):e38582. doi: 10.1016/j.heliyon.2024.e38582. eCollection 2024 Oct 15.
Gastric cancer, a common and severe malignancy, is associated with unfavorable outcomes and limited therapeutic options. The exploration of the potential link between plasma histone-modifying enzymes and gastric cancer through Mendelian randomization (MR) analysis offers an opportunity to identify new therapeutic targets and biomarkers. In this study, data on plasma histone-modifying enzymes were obtained from the International Working Unit Open genome-wide association studies project, and summary statistics of gastric cancer from the FinnGen study were analyzed. Forward and inverse MR were performed to determine the causal relationship between plasma histone-modifying enzymes and gastric cancer. The principal methodology for MR is the inverse variance weighted (IVW) method. Additionally, a sensitivity analysis was performed to determine the robustness of the findings. Finally, bioinformatics was used for the preliminary functional analysis. Our forward MR analysis revealed that the plasma Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L) was positively associated with gastric cancer risk, and the histone-lysine N-methyltransferase SETMAR (SETMAR) was negatively associated. Inverse MR analysis revealed that gastric cancer incidence was negatively correlated with the expression of plasma histone acetyltransferase KAT6A (KAT6A). These findings were consistent across different statistical methods and were deemed unlikely to have been distorted by horizontal pleiotropy. Furthermore, bioinformatics analysis indicated that ASH2L, SETMAR, and KAT6A are differentially expressed in various tumors and are significantly correlated with both the prognosis of gastric cancer and the infiltration of various immune cells. Thus, plasma histone-modifying enzymes may be causally linked to gastric cancer, and ASH2L, SETMAR, and KAT6A could play crucial roles as biomarkers and therapeutic targets in managing gastric cancer.
胃癌是一种常见且严重的恶性肿瘤，其预后不佳且治疗选择有限。通过孟德尔随机化（MR）分析探索血浆组蛋白修饰酶与胃癌之间的潜在联系，为识别新的治疗靶点和生物标志物提供了契机。在本研究中，血浆组蛋白修饰酶的数据来自国际合作组开放全基因组关联研究项目，胃癌的汇总统计数据来自芬兰基因组研究并进行了分析。采用正向和反向MR来确定血浆组蛋白修饰酶与胃癌之间的因果关系。MR的主要方法是逆方差加权（IVW）法。此外，进行了敏感性分析以确定研究结果的稳健性。最后，利用生物信息学进行初步功能分析。我们的正向MR分析显示，血浆Set1/Ash2组蛋白甲基转移酶复合物亚基ASH2（ASH2L）与胃癌风险呈正相关，而组蛋白赖氨酸N-甲基转移酶SETMAR（SETMAR）与胃癌风险呈负相关。反向MR分析显示，胃癌发病率与血浆组蛋白乙酰转移酶KAT6A（KAT6A）的表达呈负相关。这些发现通过不同的统计方法均保持一致，且不太可能因水平多效性而产生偏差。此外，生物信息学分析表明，ASH2L、SETMAR和KAT6A在各种肿瘤中存在差异表达，并且与胃癌的预后以及各种免疫细胞的浸润均显著相关。因此，血浆组蛋白修饰酶可能与胃癌存在因果联系，而ASH2L、SETMAR和KAT6A可能作为生物标志物和治疗靶点在胃癌管理中发挥关键作用。
