Piergentili Roberto, Marinelli Enrico, De Paola Lina, Cucinella Gaspare, Billone Valentina, Zaami Simona, Gullo Giuseppe
Institute of Molecular Biology and Pathology, Italian National Research Council (CNR-IBPM), 00185 Rome, Italy.
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy.
Int J Mol Sci. 2025 Jul 29;26(15):7306. doi: 10.3390/ijms26157306.
Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Risk factors for EC include metabolic alterations (obesity, metabolic syndrome, insulin resistance), hormonal imbalance, age at menopause, reproductive factors, and inherited conditions, such as Lynch syndrome. For the inherited forms, several genes had been implicated in EC occurrence and development, such as , , , , , , , , , and , all mutated at high frequency in EC patients. However, gene function impairment is not necessarily caused by mutations in the coding sequence of these and other genes. Gene function alteration may also occur through post-transcriptional control of messenger RNA translation, frequently caused by microRNA action, but transcriptional impairment also has a profound impact. Here, we review how chromatin modifications change the expression of genes whose impaired function is directly related to EC etiopathogenesis. Chromatin modification plays a central role in EC. The modification of chromatin structure alters the accessibility of genes to transcription factors and other regulatory proteins, thus altering the intracellular protein amount. Thus, DNA structural alterations may impair gene function as profoundly as mutations in the coding sequences. Hence, its central importance is in the diagnostic and prognostic evaluation of EC patients, with the caveat that chromatin alteration is often difficult to identify and needs investigations that are specific and not broadly used in common clinical practice. The different phases of the healthy endometrium menstrual cycle are characterized by differential gene expression, which, in turn, is also regulated through epigenetic mechanisms involving DNA methylation, histone post-translational modifications, and non-coding RNA action. From a medicolegal and policy-making perspective, the implications of using epigenetics in cancer care are briefly explored as well. Epigenetics in endometrial cancer is not only a topic of biomedical interest but also a crossroads between science, ethics, law, and public health, requiring integrated approaches and careful regulation.
子宫内膜癌（EC）是发达国家最常见的妇科恶性肿瘤。EC的风险因素包括代谢改变（肥胖、代谢综合征、胰岛素抵抗）、激素失衡、绝经年龄、生殖因素以及遗传性疾病，如林奇综合征。对于遗传性形式，已有多个基因与EC的发生和发展有关，如 、 、 、 、 、 、 、 、 ，这些基因在EC患者中均有高频突变。然而，基因功能障碍不一定是由这些基因和其他基因编码序列中的突变引起的。基因功能改变也可能通过信使核糖核酸翻译的转录后控制发生，这通常由微小RNA作用引起，但转录损伤也有深远影响。在这里，我们综述染色质修饰如何改变那些功能受损与EC病因直接相关的基因的表达。染色质修饰在EC中起核心作用。染色质结构的修饰改变了基因对转录因子和其他调节蛋白的可及性，从而改变细胞内蛋白质的量。因此，DNA结构改变可能像编码序列中的突变一样严重损害基因功能。因此，其在EC患者诊断和预后评估中的核心重要性在于，需要注意的是，染色质改变往往难以识别，需要特定的研究，而这些研究在普通临床实践中并未广泛应用。健康子宫内膜月经周期的不同阶段以差异基因表达为特征，而差异基因表达又通过涉及DNA甲基化、组蛋白翻译后修饰和非编码RNA作用的表观遗传机制进行调节。从法医学和政策制定的角度，我们也简要探讨了表观遗传学在癌症治疗中的应用。子宫内膜癌中的表观遗传学不仅是生物医学关注的话题，也是科学、伦理、法律和公共卫生的交叉点，需要综合方法和谨慎监管。
