State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development , School of Life Sciences , Institute of Biomedical Sciences , Human Phenome Institute , Zhongshan Hospital , Fudan University , Shanghai , China.
Department of Pathology , Zhongshan Hospital , Fudan University , Shanghai , China.
Hepatology. 2023 Feb 1;77(2):411-429. doi: 10.1002/hep.32624. Epub 2022 Jul 5.
Cholangiocarcinoma (CCA) is a highly heterogeneous cancer with limited understanding and few effective therapeutic approaches. We aimed at providing a proteogenomic CCA characterization to inform biological processes and treatment vulnerabilities.
Integrative genomic analysis with functional validation uncovered biological perturbations downstream of driver events including DPCR1 , RBM47 mutations, SH3BGRL2 copy number alterations, and FGFR2 fusions in CCA. Proteomic clustering identified three subtypes with distinct clinical outcomes, molecular features, and potential therapeutics. Phosphoproteomics characterized targetable kinases in CCA, suggesting strategies for effective treatment with CDK and MAPK inhibitors. Patients with CCA with HBV infection showed increased antigen processing and presentation (APC) and T cell infiltration, conferring a favorable prognosis compared with those without HBV infection. The characterization of extrahepatic CCA recommended the feasible application of vascular endothelial-derived growth factor inhibitors. Multiomics profiling presented distinctive molecular characteristics of the large bile duct and the small bile duct of intrahepatic CCA. The immune landscape further revealed diverse tumor immune microenvironments, suggesting immune subtypes C1 and C5 might benefit from immune checkpoint therapy. TCN1 was identified as a potential CCA prognostic biomarker, promoting cell growth by enhancing vitamin B12 metabolism.
We characterized the proteogenomic landscape of 217 CCAs with 197 paired normal adjacent tissues and identified their subtypes and potential therapeutic targets. The multiomics analyses with other databases and some functional validations have indicated strategies regarding the clinical, biological, and therapeutic approaches to the management of CCA.
胆管癌（CCA）是一种高度异质性的癌症，目前对其了解有限，治疗方法也很有限。我们旨在提供一个蛋白质基因组学的 CCA 特征描述，以阐明生物学过程和治疗弱点。
通过整合基因组分析和功能验证，我们发现了驱动事件（包括 DPCR1、RBM47 突变、SH3BGRL2 拷贝数改变和 FGFR2 融合）下游的生物学扰动。蛋白质组聚类鉴定了三种具有不同临床结局、分子特征和潜在治疗方法的亚型。磷酸化蛋白质组学鉴定了 CCA 中可靶向的激酶，提示了使用 CDK 和 MAPK 抑制剂进行有效治疗的策略。乙型肝炎病毒（HBV）感染的 CCA 患者表现出增加的抗原加工和呈递（APC）和 T 细胞浸润，与没有 HBV 感染的患者相比，预后较好。肝外 CCA 的特征分析推荐了可行的血管内皮衍生生长因子抑制剂的应用。多组学分析呈现了肝内 CCA 的大胆管和小胆管的独特分子特征。免疫景观进一步揭示了不同的肿瘤免疫微环境，提示免疫亚型 C1 和 C5 可能受益于免疫检查点治疗。TCN1 被鉴定为潜在的 CCA 预后生物标志物，通过增强维生素 B12 代谢促进细胞生长。
我们对 217 例 CCA 及其 197 对配对的正常相邻组织进行了蛋白质基因组学特征描述，并鉴定了它们的亚型和潜在的治疗靶点。多组学分析与其他数据库和一些功能验证相结合，为 CCA 的临床、生物学和治疗管理提供了策略。
