Lorenzini Eugenia, Ciarrocchi Alessia, Torricelli Federica
Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy.
J Clin Med. 2021 Jun 2;10(11):2470. doi: 10.3390/jcm10112470.
Malignant pleural mesothelioma (MPM) is a clinical emergency of our time. Being strongly associated with asbestos exposure, incidence of this cancer is ramping up these days in many industrialized countries and it will soon start to increase in many developing areas where the use of this silicate derivate is still largely in use. Deficiency of reliable markers for the early identification of these tumors and the limited efficacy of the currently available therapeutic options are the basis of the impressive mortality rate of MPM. These shortcomings reflect the very poor information available about the molecular basis of this disease. Results of the recently released deep profiling studies point to the epigenome as a central element in MPM development and progression. First, MPM is characterized by a low mutational burden and a highly peculiar set of mutations that hits almost exclusively epigenetic keepers or proteins controlling chromatin organization and function. Furthermore, asbestos does not seem to be associated with a distinctive mutational signature, while the precise mapping of epigenetic changes caused by this carcinogen has been defined, suggesting that alterations in epigenetic features are the driving force in the development of this disease. Last but not least, consistent evidence also indicates that, in the setting of MPM, chromatin rewiring and epigenetic alterations of cancer cells heavily condition the microenvironment, including the immune response. In this review we aim to point to the relevance of the epigenome in MPM and to highlight the dependency of this tumor on chromatin organization and function. We also intend to discuss the opportunity of targeting these mechanisms as potential therapeutic options for MPM.
恶性胸膜间皮瘤（MPM）是当今的一种临床急症。由于与石棉暴露密切相关，如今在许多工业化国家，这种癌症的发病率正在上升，而且在许多仍大量使用这种硅酸盐衍生物的发展中地区，其发病率很快也将开始上升。缺乏用于早期识别这些肿瘤的可靠标志物以及现有治疗方案疗效有限，是MPM死亡率高得惊人的原因。这些缺点反映出关于这种疾病分子基础的信息非常匮乏。最近发布的深度分析研究结果表明，表观基因组是MPM发生和发展的核心要素。首先，MPM的特点是突变负担低，且有一组高度独特的突变，这些突变几乎只影响表观遗传调控因子或控制染色质组织和功能的蛋白质。此外，石棉似乎与独特的突变特征无关，而这种致癌物引起的表观遗传变化的精确图谱已经确定，这表明表观遗传特征的改变是这种疾病发展的驱动力。最后但同样重要的是，一致的证据还表明，在MPM的情况下，癌细胞的染色质重塑和表观遗传改变严重影响微环境，包括免疫反应。在这篇综述中，我们旨在指出表观基因组在MPM中的相关性，并强调这种肿瘤对染色质组织和功能的依赖性。我们还打算讨论将这些机制作为MPM潜在治疗选择的可能性。
