Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
Department of Pathology and Cell Biology, Columbia University Irvine Medical Center, New York, NY, United States of America.
Gynecol Oncol. 2023 May;172:54-64. doi: 10.1016/j.ygyno.2023.03.010. Epub 2023 Mar 21.
Chromatin remodeling genes (CRGs) encode components of epigenetic regulatory mechanisms and alterations in these genes have been identified in several tumor types, including gynecologic cancers. In this study, we sought to investigate the prevalence and clinicopathological associations of CRG alterations in endometrial carcinoma (EC).
We performed a retrospective analysis of 660 ECs sequenced using a clinical massively parallel sequencing assay targeting up to 468 genes, including 25 CRGs, and defined the presence of somatic CRG alterations. Clinicopathologic features were obtained for all cases. Immunohistochemical interrogation of ARID1A and PTEN proteins was performed in a subset of samples.
Of the 660 ECs sequenced, 438 (66.4%) harbored CRG alterations covered by our panel. The most commonly altered CRG was ARID1A (46%), followed by CTCF (21%), KMT2D (18%), KMT2B (17%), BCOR (16%), ARID1B (12%) and SMARCA4 (11%). We found that ARID1A genetic alterations were preferentially bi-allelic and often corresponded to altered ARID1A protein expression in ECs. We further observed that ARID1A alterations were often subclonal when compared to PTEN alterations, which were primarily clonal in ECs harboring both mutations. Finally, CRG alterations were associated with an increased likelihood of myometrial and lymphovascular invasion in endometrioid ECs.
CRG alterations are common in EC and are associated with clinicopathologic features and likely play a crucial role in EC.
染色质重塑基因（CRGs）编码表观遗传调控机制的组成部分，这些基因的改变已在多种肿瘤类型中被发现，包括妇科癌症。在这项研究中，我们试图调查子宫内膜癌（EC）中 CRG 改变的流行率和临床病理关联。
我们对 660 例使用靶向多达 468 个基因（包括 25 个 CRG）的临床大规模平行测序检测进行了回顾性分析，并定义了体细胞 CRG 改变的存在。对所有病例均获得了临床病理特征。在一部分样本中进行了 ARID1A 和 PTEN 蛋白的免疫组织化学检测。
在测序的 660 例 EC 中，有 438 例（66.4%）存在我们的研究小组涵盖的 CRG 改变。改变最常见的 CRG 是 ARID1A（46%），其次是 CTCF（21%）、KMT2D（18%）、KMT2B（17%）、BCOR（16%）、ARID1B（12%）和 SMARCA4（11%）。我们发现 ARID1A 基因改变是双等位基因的，并且经常与 EC 中 ARID1A 蛋白表达的改变相对应。我们还观察到，与主要是克隆的 ARID1A 改变相比，PTEN 改变通常是亚克隆的，而在同时存在这两种突变的 EC 中，PTEN 改变主要是克隆的。最后，CRG 改变与子宫内膜样 EC 中肌层和脉管侵犯的可能性增加相关。
CRG 改变在 EC 中很常见，与临床病理特征相关，并可能在 EC 中发挥关键作用。
