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建立起来。在本研究中，我们对158名中国EC患者进行了下一代测序分析（74名接受EC相关20基因面板测试，84名接受扩展面板测试）。其中，91名患者使用扩展面板进行了生殖系突变测试。此外，我们利用TCGA和MSKCC的公共数据集比较了中国EC患者与西方EC患者之间的基因组差异。我们使用CPTAC和TCGA的蛋白质组学和转录组学数据进行非监督聚类分析，以鉴定分子亚型。在分析的158例患者中，有显著的多数（85.4%）至少存在一种体细胞变异，其中最常见的变异发生在PTEN、PIK3CA、TP53和ARID1A基因中。这些基因组变异主要富集在PI3K、细胞周期、RAS/RAF/MAPK、表观遗传修饰/染色质重塑和DNA损伤修复（DDR）信号通路中。此外，我们在七个基因中鉴定出十名个体（11.0%）携带致病或可能致病的生殖系变异，其中DDR通路参与最为突出。与西方EC患者相比，中国EC患者在AKT1、MET、PMS2、PIK3R1和CTCF基因的患病率显示差异。值得注意的是，69.6%的中国EC患者被鉴定出可行治疗的基因变异。此外，我们发现在ARID1A野生型患者中存在新的分子亚型，其特点是预后较差，TP53基因变异较多，而PTEN和PIK3CA基因变异较少。此亚型还显示出较高数量的巨噬细胞和活化树突细胞。我们的研究为中国EC患者的独特生殖系和体细胞基因组特征提供了宝贵的洞察，加深了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患者的分子异质性存在，为这一亚组的复杂性提供了启示。© 2023. 由Springer Nature下属的BioMed Central Ltd.发表。

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.© 2023. BioMed Central Ltd., part of Springer Nature.