Abstract：
The hyperplasia-carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH-AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the PTEN mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
摘要：
增生-癌序列是子宫内膜癌的逐步致瘤程序，其中正常子宫内膜上皮通过非非典型子宫内膜增生（NAEH）和非典型子宫内膜增生（AEH）成为肿瘤，在没有反对的雌激素的影响下。已知NAEH和AEH表现出多克隆和单克隆细胞生长，分别；然而，除了局灶性PTEN蛋白丢失，在细胞转变过程中发生的遗传和表观遗传改变在很大程度上仍然未知。我们试图探索促进NAEH-AEH转变的潜在分子机制，并鉴定有助于区分这两种状态的分子标记。我们对596个基因的编码外显子进行了靶组测序，包括96个子宫内膜癌驱动基因，通过宏观或微观解剖从30例子宫内膜组织中分别收集48个NAEH和44个AEH病变的DNA甲基化微阵列。测序分析显示在AEH样品中获得了PTEN突变和肿瘤细胞的克隆扩增。Further,在过渡期间，DNA甲基化改变的特征是启动子/增强子区和CpG岛的超甲基化，以及与子宫内膜细胞分化和/或肿瘤发生相关的转录因子的DNA结合区域的低甲基化和高甲基化，包括FOXA2、SOX17和HAND2。鉴定的区分NAEH和AEH病变的DNA甲基化特征在具有适度辨别能力的验证队列中是可再现的。这些发现不仅支持从NAEH到AEH的转变是子宫内膜上皮肿瘤细胞转化的重要步骤，而且还提供了对肿瘤发生程序分子机制的深刻见解。©2024作者由JohnWiley＆SonsLtd代表英国和爱尔兰病理学会出版的病理学杂志。
