@article{9e39405be1de4a3fb5732dc5e0e4f7a6,
title = "Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma",
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.",
keywords = "FGFR2 fusion, intrahepatic cholangiocarcinoma, molecular subgroups, oncogenic drivers, prognostic biomarkers, proteogenomics",
author = "Liangqing Dong and Dayun Lu and Ran Chen and Youpei Lin and Hongwen Zhu and Zhou Zhang and Shangli Cai and Peng Cui and Guohe Song and Dongning Rao and Xinpei Yi and Yingcheng Wu and Nixue Song and Fen Liu and Yunhao Zou and Shu Zhang and Xiaoming Zhang and Xiaoying Wang and Shuangjian Qiu and Jian Zhou and Shisheng Wang and Xu Zhang and Yongyong Shi and Daniel Figeys and Li Ding and Pei Wang and Bing Zhang and Henry Rodriguez and Qiang Gao and Daming Gao and Hu Zhou and Jia Fan",
note = "Funding Information: This work was supported by the National Key Research and Development Program of China (grants 2020YFE0202200 , 2020YFA0803203 , 2017YFC1700200 , 2020YFA0509000 , and 2019YFA0802102 ), the National Natural Science Foundation of China (grants 82130077 , 81961128025 , 91859105 , 81925029 , 91853130 , 81790253 , and 82002514 ), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDB19020203 ), Research Projects from the Science and Technology Commission of Shanghai Municipality (grants 21JC1410100 , 20JC1418900 , 19XD1420700 , 20XD1424900 , and 20YF1407400 ), the Shanghai Municipal Health Commission Collaborative Innovation Cluster Project ( 2019CXJQ02 ), Shanghai Municipal Science and Technology Major Project, CAS project for young scientists in basic research ( YSBR-014 ). We thank Dr. Fuchu He (Beijing Institute of Lifeomics, Beijing) for expert guidance and insightful suggestions to our study. We also thank Mr. Bing Li, Guoqiang Wang, and Xuan Lin (Burning Rock Biotech) for the assistance of bioinformatics analysis. We thank Mr. Xu Ding (TinyGene Bio-Tech Co., Ltd., Shanghai) for the 16S rRNA sequencing. This work was done under the auspices of a Memorandum of Understanding between the Shanghai Institute of Materia Medica, Chinese Academy of Science, Fudan University, and the US National Cancer Institute's Office of Cancer Clinical Proteomics Research (Clinical Proteomic Tumor Analysis Consortium—CPTAC), as well as under the auspices of the US National Cancer Institute's International Cancer Proteogenome Consortium (ICPC). CPTAC collaborates with international organizations/institutions to accelerate the understanding of the molecular basis of cancer through the application of proteogenomics, standards development, and publicly available datasets. Funding Information: This work was supported by the National Key Research and Development Program of China (grants 2020YFE0202200, 2020YFA0803203, 2017YFC1700200, 2020YFA0509000, and 2019YFA0802102), the National Natural Science Foundation of China (grants 82130077, 81961128025, 91859105, 81925029, 91853130, 81790253, and 82002514), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDB19020203), Research Projects from the Science and Technology Commission of Shanghai Municipality (grants 21JC1410100, 20JC1418900, 19XD1420700, 20XD1424900, and 20YF1407400), the Shanghai Municipal Health Commission Collaborative Innovation Cluster Project (2019CXJQ02), Shanghai Municipal Science and Technology Major Project, CAS project for young scientists in basic research (YSBR-014). We thank Dr. Fuchu He (Beijing Institute of Lifeomics, Beijing) for expert guidance and insightful suggestions to our study. We also thank Mr. Bing Li, Guoqiang Wang, and Xuan Lin (Burning Rock Biotech) for the assistance of bioinformatics analysis. We thank Mr. Xu Ding (TinyGene Bio-Tech Co. Ltd. Shanghai) for the 16S rRNA sequencing. This work was done under the auspices of a Memorandum of Understanding between the Shanghai Institute of Materia Medica, Chinese Academy of Science, Fudan University, and the US National Cancer Institute's Office of Cancer Clinical Proteomics Research (Clinical Proteomic Tumor Analysis Consortium?CPTAC), as well as under the auspices of the US National Cancer Institute's International Cancer Proteogenome Consortium (ICPC). CPTAC collaborates with international organizations/institutions to accelerate the understanding of the molecular basis of cancer through the application of proteogenomics, standards development, and publicly available datasets. Conceptualization, J.F. H. Zhou, D.G. Q.G. and H.R.; methodology, Q.G. L. Dong, D.L. R.C. Y.L. and Z.Z.; formal analysis, L. Dong, D.L. Q.G. Y.L. H. Zhu, N.S. S.W. S.C. P.C. G.S. D.R. X.Y. S.Z. S.Q. X.Z. Y.S. D.F. P.W. L. Ding, and B.Z.; investigation, L. Dong, D.L. R.C. Y.L. F.L. Y.Z. and Q.G.; resources, J.F. H. Zhou, D.G. Q.G. X.W. and J.Z.; data curation, Q.G. L. Dong, and D.L.; writing, Q.G. L. Dong, D.L. R.C. Z.Z. D.G. H. Zhou, and J.F.; visualization, L. Dong, D.L. Y.W. P.C. and Z.Z.; supervision, J.F. H. Zhou, D.G. Q.G. and H.R.; funding acquisition, J.F. H. Zhou, D.G. L. Dong, and Q.G. Z.Z. S.C. and P.C. are employees of Burning Rock Biotech. Other authors declare no potential conflict of interest. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2022",
month = jan,
day = "10",
doi = "10.1016/j.ccell.2021.12.006",
language = "English",
volume = "40",
pages = "70--87.e15",
journal = "Cancer Cell",
issn = "1535-6108",
number = "1",
}