Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma
Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma
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蛋白质组学特征鉴定了肝内胆管癌的临床相关亚组。
DOI：
10.1016/j.ccell.2021.12.006
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发表时间：
2022-01-10
期刊：
影响因子：
50.3
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Dong, Liangqing;Lu, Dayun;Fan, Jia
我们使用262例患者的成对肿瘤和邻近肝组织进行了肝内胆管细胞癌（iCCA）的蛋白质基因组学表征。综合蛋白基因组学分析优先考虑遗传畸变，并揭示了iCCA发病机制的标志。黄曲霉毒素信号与肿瘤发生、增殖和免疫抑制相关。突变相关的信号传导谱显示TP 53和KRAS共突变可能通过整合素-FAK-SRC途径促进iCCA转移。FGFR 2融合激活Rho GT3通路，可能是新抗原的潜在来源。蛋白质组学分析确定了具有亚组特异性生物标志物的四个患者亚组（S1-S4）。这些蛋白质组亚组在预后、遗传改变、微环境失调、肿瘤微生物群组成和潜在治疗方面具有不同的特征。SLC 16 A3和HKDC 1被进一步鉴定为与iCCA细胞的代谢重编程相关的潜在预后生物标志物。这项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的资源。
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.