PDF(Pubmed)
Abstract：
Uterine leiomyomas (ULs) are the most common benign tumor of the uterus. They can be associated with symptoms including abnormal uterine bleeding, pelvic pain, urinary frequency, and pregnancy complications. Despite the high prevalence of UL, its underlying pathophysiology mechanisms have historically been poorly understood. Several mechanisms of pathogenesis have been suggested, implicating various genes, growth factors, cytokines, chemokines, and microRNA aberrations. The purpose of this study is to summarize the current research on the relationship of genetics with UL. Specifically, we performed a literature review of published studies to identify how genetic aberrations drive pathophysiology, epidemiology, and therapeutic approaches of UL. With regards to pathophysiology, research has identified MED12 mutations, HMGA2 overexpression, fumarate hydratase deficiency, and cytogenetic abnormalities as contributors to the development of UL. Additionally, epigenetic modifications, such as histone acetylation and DNA methylation, have been identified as contributing to UL tumorigenesis. Specifically, UL stem cells have been found to contain a unique DNA methylation pattern compared to more differentiated UL cells, suggesting that DNA methylation has a role in tumorigenesis. On a population level, genome-wide association studies (GWASs) and epidemiologic analyses have identified 23 genetic loci associated with younger age at menarche and UL growth. Additionally, various GWASs have investigated genetic loci as potential drivers of racial disparities in UL incidence. For example, decreased expression of Cytohesin 4 in African Americans has been associated with increased UL risk. Recent studies have investigated various therapeutic options, including ten-eleven translocation proteins mediating DNA methylation, adenovirus vectors for drug delivery, and \"suicide gene therapy\" to induce apoptosis. Overall, improved understanding of the genetic and epigenetic drivers of UL on an individual and population level can propel the discovery of novel therapeutic options.
摘要：
子宫平滑肌瘤（ULs）是子宫最常见的良性肿瘤。它们可能与包括异常子宫出血在内的症状有关，盆腔疼痛,尿频,妊娠并发症。尽管UL的患病率很高，其潜在的病理生理机制历来知之甚少。已经提出了几种发病机制，牵涉到各种基因，生长因子，细胞因子,趋化因子,和microRNA畸变。本研究旨在总结遗传学与UL关系的研究现状。具体来说,我们对已发表的研究进行了文献综述，以确定遗传畸变如何驱动病理生理学，流行病学,和UL的治疗方法。关于病理生理学，研究已经确定了MED12突变，HMGA2过表达,富马酸水合酶缺乏症，和细胞遗传学异常是UL发展的贡献者。此外,表观遗传修饰,如组蛋白乙酰化和DNA甲基化，已被确定为有助于UL肿瘤发生。具体来说,与更分化的UL细胞相比，UL干细胞已被发现含有独特的DNA甲基化模式。表明DNA甲基化在肿瘤发生中起作用。在人口层面上，全基因组关联研究(GWASs)和流行病学分析确定了23个与初潮和UL生长年龄较小相关的遗传基因座.此外,各种GWASs已经调查了作为UL发病率种族差异的潜在驱动因素的遗传基因座.例如,在非裔美国人中,Cytohesin4的表达降低与UL风险增加相关.最近的研究调查了各种治疗选择，包括十一个介导DNA甲基化的易位蛋白，用于药物递送的腺病毒载体，和“自杀基因疗法”诱导细胞凋亡。总的来说,在个体和群体水平上对UL的遗传和表观遗传驱动因素的更好理解可以推动新的治疗选择的发现。
