Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, 200032, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
BMC Cancer. 2023 Sep 20;23(1):888. doi: 10.1186/s12885-023-11382-4.
Endometrial carcinoma (EC) is one of the most commonly diagnosed gynecologic malignancy in China. However, the genetic profile of Chinese EC patients has not been well established yet.
In current study, 158 Chinese EC patients were subjected to next-generation sequencing assay (74 took testing of EC-related 20-genes panel, and 84 took the expanded panel). Of the 158 patients, 91 patients were performed germline mutation testing using the expanded panel. Moreover, the public datasets from TCGA and MSKCC were utilized to compare the genomic differences between Chinese and Western EC patients. The proteomic and transcriptomic from CPTAC and TCGA were derived and performed unsupervised clustering to identify molecular subtypes.
Among the 158 patients analyzed, a significant majority (85.4%) exihibited at least one somatic alteration, with the most prevalent alterations occurring in PTEN, PIK3CA, TP53, and ARID1A. These genomic alterations were mainly enriched in the PI3K, cell cycle, RAS/RAF/MAPK, Epigenetic modifiers/Chromatin remodelers, and DNA damage repair (DDR) signaling pathways. Additionally, we identified ten individuals (11.0%) with pathogenic or likely pathogenic germline alterations in seven genes, with the DDR pathway being predominantly involved. Compared to Western EC patients, Chinese EC patients displayed different prevalence in AKT1, MET, PMS2, PIK3R1, and CTCF. Notably, 69.6% of Chinese EC patients were identified with actionable alterations. In addition, we discovered novel molecular subtypes in ARID1A wild-type patients, characterized by an inferior prognosis, higher TP53 but fewer PTEN and PIK3CA alterations. Additionally, this subtype exhibited a significantly higher abundance of macrophages and activated dendritic cells.
Our study has contributed valuable insights into the unique germline and somatic genomic profiles of Chinese EC patients, enhancing our understanding of their biological characteristics and potential therapeutic avenues. Furthermore, we have highlighted the presence of molecular heterogeneity in ARID1A-wild type EC patients, shedding light on the complexity of this subgroup.
子宫内膜癌（EC）是中国最常见的妇科恶性肿瘤之一。然而，中国 EC 患者的遗传特征尚未得到充分确立。
在本研究中，对 158 名中国 EC 患者进行了下一代测序检测（74 名患者进行了与 EC 相关的 20 个基因面板检测，84 名患者进行了扩展面板检测）。在 158 名患者中，91 名患者使用扩展面板进行了种系突变检测。此外，还利用 TCGA 和 MSKCC 的公共数据集比较了中西方 EC 患者的基因组差异。从 CPTAC 和 TCGA 获得了蛋白质组学和转录组学数据，并进行了无监督聚类以鉴定分子亚型。
在分析的 158 名患者中，绝大多数（85.4%）至少存在一种体细胞改变，最常见的改变发生在 PTEN、PIK3CA、TP53 和 ARID1A 中。这些基因组改变主要富集在 PI3K、细胞周期、RAS/RAF/MAPK、表观遗传修饰物/染色质重塑剂和 DNA 损伤修复（DDR）信号通路中。此外，我们在七个基因中发现了 10 名（11.0%）个体存在致病性或可能致病性的种系改变，其中 DDR 通路占主导地位。与西方 EC 患者相比，中国 EC 患者在 AKT1、MET、PMS2、PIK3R1 和 CTCF 中的发生率不同。值得注意的是，69.6%的中国 EC 患者存在可治疗的改变。此外，我们在 ARID1A 野生型患者中发现了新的分子亚型，其特征为预后较差，TP53 较高，但 PTEN 和 PIK3CA 改变较少。此外，这种亚型的巨噬细胞和激活的树突状细胞的丰度明显更高。
本研究深入探讨了中国 EC 患者独特的种系和体细胞基因组特征，增强了我们对其生物学特征和潜在治疗途径的理解。此外，我们还强调了 ARID1A 野生型 EC 患者中存在分子异质性，揭示了这一亚组的复杂性。
