蛋白质基因组学特征鉴定出肝内胆管癌的临床相关亚组。

Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma.

作者信息

Dong Liangqing, Lu Dayun, Chen Ran, Lin Youpei, Zhu Hongwen, Zhang Zhou, Cai Shangli, Cui Peng, Song Guohe, Rao Dongning, Yi Xinpei, Wu Yingcheng, Song Nixue, Liu Fen, Zou Yunhao, Zhang Shu, Zhang Xiaoming, Wang Xiaoying, Qiu Shuangjian, Zhou Jian, Wang Shisheng, Zhang Xu, Shi Yongyong, Figeys Daniel, Ding Li, Wang Pei, Zhang Bing, Rodriguez Henry, Gao Qiang, Gao Daming, Zhou Hu, Fan Jia

机构信息

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China.

Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China.

出版信息

Cancer Cell. 2022 Jan 10;40(1):70-87.e15. doi: 10.1016/j.ccell.2021.12.006. Epub 2021 Dec 30.

DOI:10.1016/j.ccell.2021.12.006

PMID:34971568

Abstract

We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1-S4) with subgroup-specific biomarkers. These proteomic subgroups had distinct features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.

摘要

我们使用来自262例患者的配对肿瘤组织和邻近肝组织，对肝内胆管癌（iCCA）进行了蛋白质基因组学特征分析。综合蛋白质基因组学分析确定了基因畸变的优先级，并揭示了iCCA发病机制的特征。黄曲霉毒素特征与肿瘤起始、增殖和免疫抑制相关。突变相关的信号通路分析表明，TP53和KRAS共突变可能通过整合素-FAK-SRC途径促进iCCA转移。FGFR2融合激活了Rho GTPase途径，可能是新抗原的潜在来源。蛋白质组学分析确定了四个患者亚组（S1-S4），各亚组具有特定的生物标志物。这些蛋白质组学亚组在预后、基因改变、微环境失调、肿瘤微生物群组成和潜在治疗方法方面具有不同特征。SLC16A3和HKDC1被进一步确定为与iCCA细胞代谢重编程相关的潜在预后生物标志物。本研究为研究人员和临床医生进一步确定iCCA的分子发病机制和治疗机会提供了宝贵资源。