Xi Qian, Kage Hidenori, Ogawa Miho, Matsunaga Asami, Nishijima Akira, Sone Kenbun, Kawana Kei, Oda Katsutoshi
Division of Integrative Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan.
Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan.
Cancers (Basel). 2023 Dec 27;16(1):136. doi: 10.3390/cancers16010136.
This study aimed to comprehensively clarify the genomic landscape and its association with tumor mutational burden-high (TMB-H, ≥10 mut/Mb) and microsatellite instability-high (MSI-H) in endometrial, cervical, and ovarian cancers. We obtained genomic datasets of a comprehensive genomic profiling test, FoundationOne CDx, with clinical information using the "Center for Cancer Genomics and Advanced Therapeutics" (C-CAT) database in Japan. Patients can undergo the tests only after standardized treatments under universal health insurance coverage. Endometrial cancers were characterized by a high frequency of TMB-H and MSI-H, especially in endometrioid carcinomas. The lower ratio of exonuclease mutations and the higher ratio of mutations compared to previous reports suggested the prognostic effects of the molecular subtypes. Among the 839 cervical cancer samples, frequent mutations of , , , , , and were observed in adenocarcinomas, whereas the ratio of TMB-H was significantly higher in squamous cell carcinomas. Among the 1606 ovarian cancer samples, genomic profiling of serous, clear cell, endometrioid, and mucinous carcinomas was characterized. Pathogenic mutations in the exonuclease domain were associated with high TMB, and the mutation ratio was low in both cervical and ovarian cancers. The C-CAT database is useful for determining the mutational landscape of each cancer type and histological subtype. As the dataset is exclusively collected from patients after the standardized treatments, the information on "druggable" alterations highlights the unmet needs for drug development in major gynecological cancers.
本研究旨在全面阐明子宫内膜癌、宫颈癌和卵巢癌的基因组格局及其与肿瘤突变负荷高（TMB-H，≥10个突变/Mb）和微卫星高度不稳定（MSI-H）的关联。我们使用日本的“癌症基因组学与先进治疗中心”（C-CAT）数据库，获得了具有临床信息的全面基因组分析测试FoundationOne CDx的基因组数据集。患者只有在全民健康保险覆盖下接受标准化治疗后才能进行这些测试。子宫内膜癌的特征是TMB-H和MSI-H频率较高，尤其是在子宫内膜样癌中。与先前报告相比，外切核酸酶突变比例较低，而其他突变比例较高，这表明了分子亚型的预后影响。在839份宫颈癌样本中，腺癌中观察到 、 、 、 、 和 的频繁突变，而鳞状细胞癌中TMB-H的比例显著更高。在1606份卵巢癌样本中，对浆液性、透明细胞、子宫内膜样和黏液性癌进行了基因组分析。外切核酸酶结构域的致病性突变与高TMB相关，且在宫颈癌和卵巢癌中的突变率均较低。C-CAT数据库有助于确定每种癌症类型和组织学亚型的突变格局。由于该数据集仅从标准化治疗后的患者中收集，“可靶向”改变的信息突出了主要妇科癌症药物开发中未满足的需求。
