Melatonin, an endogenous hormone, plays protective roles in cancer. In addition to regulating circadian rhythms, sleep, and neuroendocrine activity, melatonin functions in various survival pathways. However, the mechanisms of melatonin regulation in cancer remain unknown. In the present study, we performed a comprehensive characterization of melatonin regulators in 9125 tumor samples across 33 cancer types using multi-omic data from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia. In the genomic landscape, we identified the heterozygous amplification of AANAT and GPR50, and heterozygous deletion of PER3, CYP2C19, and MTNR1A as the dominant alteration events. Expression analysis revealed methylation-mediated downregulation of melatonergic regulator expression. In addition, we found that melatonergic regulator expression could be used to predict patient survival in various cancers. In depth, microRNA (miRNA) analysis revealed an miRNA-mRNA interaction network, and the deregulated miRNAs were involved in melatonin secretion and metabolism by targeting circadian clock genes. Pathway analysis showed that melatonergic regulators were associated with inhibition of apoptosis, the cell cycle, the DNA damage response, and activation of RAS/MAPK and RTK signaling pathways. Importantly, by mining the Genomics of Drug Sensitivity in Cancer database, we discovered a number of potential drugs that might target melatonergic regulators. In summary, this study revealed the genomic alteration and clinical characteristics of melatonergic regulators across 33 cancers, which might clarify the relationship between melatonin and tumorigenesis. Our findings also might provide a novel approach for the clinical treatment of cancers.

中文翻译：

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泛癌分析揭示了癌症中褪黑激素调节剂的基因组学和临床特征

褪黑激素是一种内源性激素，在癌症中起保护作用。除了调节昼夜节律、睡眠和神经内分泌活动外，褪黑激素还在各种生存途径中发挥作用。然而，褪黑激素在癌症中的调节机制仍然未知。在本研究中，我们使用来自癌症基因组图谱和癌细胞系百科全书的多组学数据，对 33 种癌症类型的 9125 个肿瘤样本中的褪黑激素调节剂进行了全面的表征。在基因组领域，我们发现了AANAT和GPR50的杂合扩增，以及PER3、CYP2C19和MTNR1A的杂合缺失作为主要的改变事件。表达分析揭示了甲基化介导的褪黑激素调节剂表达下调。此外，我们发现褪黑激素调节因子的表达可用于预测患者在各种癌症中的存活率。深入研究，microRNA (miRNA) 分析揭示了 miRNA-mRNA 相互作用网络，失调的 miRNA 通过靶向生物钟基因参与褪黑激素的分泌和代谢。通路分析表明，褪黑激素调节剂与抑制细胞凋亡、细胞周期、DNA 损伤反应以及 RAS/MAPK 和 RTK 信号通路的激活有关。重要的是，通过挖掘癌症数据库中药物敏感性的基因组学，我们发现了许多可能针对褪黑激素调节剂的潜在药物。总之，该研究揭示了 33 种癌症中褪黑激素调节剂的基因组改变和临床特征，这可能阐明褪黑激素与肿瘤发生之间的关系。我们的研究结果也可能为癌症的临床治疗提供一种新方法。