SexAnnoDB：基于多组学数据的人类癌症性别特异性调控知识库

分子水平的性别差异深刻影响癌症的生物学特性和预后。患者性别显著影响药物反应，同一药物在男性和女性中的反应存在差异。尽管已有关于人类组织性别差异的数据库，但对癌症中性别差异调控的研究仍有限，这些资源缺乏关于性别偏向分子的机制性研究。在本研究中，我们对27种癌症类型的分子差异及调控网络进行了全面分析，深入探讨性别偏差效应。分析内容包括性别偏差的竞争内源RNA网络、涉及性别偏差的RNA结合蛋白-外显子跳跃事件的调控网络、性别偏差的转录因子-基因调控网络，以及性别偏差的表达定量性状位点（eQTL）、表达甲基化定量性状位点（meQTL）、剪接QTL（sQTL）等，及性别偏差的癌症治疗药物靶点基因。这些分析结果均可在SexAnnoDB（https://ccsm.uth.edu/SexAnnoDB/）获取。分析中，我们定义了126个与癌症治疗相关的性别关联基因，其中9个基因在mRNA和蛋白水平均表现出性别偏差。特别是，S100A9为五种药物的靶点，其中钙离子已获FDA批准用于结肠癌和直肠癌的治疗。转录因子（TF）-基因调控网络分析显示，SARC男性组中的4个TF调控S100A9，并上调其表达。在KIRP女性患者中，启动子区域的甲基化状态仅与S100A9的表达相关，过度甲基化抑制S100A9的表达，导致其在女性患者中的下调。综合网络和关联分析表明，转录组水平的性别差异部分源自相应的性别偏差的表观遗传和遗传分子。总体而言，SexAnnoDB提供了一个学科特异的搜索平台，有助于基础实验研究者或临床医师制定个性化治疗方案。

Sexual differences across molecular levels profoundly impact cancer biology and outcomes. Patient gender significantly influences drug responses, with divergent reactions between men and women to the same drugs. Despite databases on sex differences in human tissues, understanding regulations of sex disparities in cancer is limited. These resources lack detailed mechanistic studies on sex-biased molecules.In this study, we conducted a comprehensive examination of molecular distinctions and regulatory networks across 27 cancer types, delving into sex-biased effects. Our analyses encompassed sex-biased competitive endogenous RNA networks, regulatory networks involving sex-biased RNA binding protein-exon skipping events, sex-biased transcription factor-gene regulatory networks, as well as sex-biased expression quantitative trait loci, sex-biased expression quantitative trait methylation, sex-biased splicing quantitative trait loci, and the identification of sex-biased cancer therapeutic drug target genes. All findings from these analyses are accessible on SexAnnoDB ( https://ccsm.uth.edu/SexAnnoDB/ ).From these analyses, we defined 126 cancer therapeutic target sex-associated genes. Among them, 9 genes showed sex-biased at both the mRNA and protein levels. Specifically, S100A9 was the target of five drugs, of which calcium has been approved by the FDA for the treatment of colon and rectal cancers. Transcription factor (TF)-gene regulatory network analysis suggested that four TFs in the SARC male group targeted S100A9 and upregulated the expression of S100A9 in these patients. Promoter region methylation status was only associated with S100A9 expression in KIRP female patients. Hypermethylation inhibited S100A9 expression and was responsible for the downregulation of S100A9 in these female patients.Comprehensive network and association analyses indicated that the sex differences at the transcriptome level were partially the result of corresponding sex-biased epigenetic and genetic molecules. Overall, SexAnnoDB offers a discipline-specific search platform that could potentially assist basic experimental researchers or physicians in developing personalized treatment plans.