Zhou Hu/Fan Jia/Gao Qiang/Gao Daming team draws a panorama of multi-omics molecular features of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver malignancy with low surgical resection rate and lack of effective targeted/immunotherapy options
.

Intrahepatic cholangiocarcinoma has a highly heterogeneous genomic mutation and tumor microenvironment that may mediate its high aggressiveness and poor prognosis
.

Therefore, there is an urgent need to conduct a "bird's-eye view" study of iCCA and draw its precise molecular map to provide a theoretical basis for systematically understanding the heterogeneity of intrahepatic cholangiocarcinoma and realizing individualized treatment
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Recently, Cancer Cell magazine published an online publication titled "Proteogenomic characterization identifies clinically The latest results of relevant subgroups of intrahepatic cholangiocarcinoma”
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This study carried out proteogenomic analysis on tumor tissues of 262 patients with iCCA.
Prognostic monitoring and personalized treatment strategies provide new ideas
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The researchers first analyzed the impact of major driver mutations in intrahepatic cholangiocarcinoma, such as TP53, KRAS, FGFR2, IDH1/2, and BAP1, on the proteome and phosphorylated proteome
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The study found that aflatoxin mutation fingerprints specifically existed in Chinese population samples, which were significantly associated with high tumor mutation burden and high NK cell infiltration
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The fusion and mutation of FGFR2 may promote the development of iCCA by activating the Rho GTPase pathway, and some of its fusion protein-derived peptides have strong immunogenicity and are potential immune antigen targets
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Subsequently, the joint team further analyzed the cis- and trans-regulatory effects of intrahepatic cholangiocarcinoma chromatin copy number variation on mRNA and protein
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Researchers divided iCCA patients into four subtypes: inflammatory (S1), interstitial (S2), metabolic (S3), and differentiated (S4) based on proteomic data.
The four subtypes have differentiated clinical features, mutation profiles, Pathway enrichment and immune signature distribution, with significant prognostic differences
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Through dimensionality reduction analysis, the team found markers that can specifically distinguish 4 subtypes, and confirmed their possibility for clinical sample typing through validation
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Ultimately, the researchers identified HKDC1 and SLC16A3 as biomarkers associated with the prognosis of iCCA
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This study was carried out under the high-quality standard framework of the International Cancer Proteogenome Consortium (ICPC) and the International Clinical Proteomic Tumor Analysis Consortium (CPTAC), aiming at the diagnosis of intrahepatic cholangiocarcinoma.
Proteogenomic analysis of the cohort
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On the one hand, this study comprehensively revealed the impact of gene mutation and chromatin variation on the proteome and phosphorylated proteome in intrahepatic cholangiocarcinoma, and proposed four molecular typing and biomarkers from the proteome level to explore tumor heterogeneity.
On the other hand, the high-quality big data generated by this study will continue to provide support for basic and clinical research on intrahepatic cholangiocarcinoma
.

　　Dr.
Liangqing Dong from Zhongshan Hospital Affiliated to Fudan University, Dayun Lu, Ph.
D.
student of Shanghai Institute of Materia Medica, Ran Chen, Ph.
D.
student of Center for Excellence in Molecular and Cell Science, Chinese Academy of Sciences, Lin Youpei, Ph.
Dr.
Zhou and Dr.
Cai Shangli are the co-first authors of this paper
.

Academician Fan Jia, Researcher Zhou Hu, Researcher Gao Daming and Professor Gao Qiang are the co-corresponding authors of this paper
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In addition, the research was supported by Academician He Fuchu of the National Center for Protein Science (Beijing), Dr.
Henry Rodriguez of the National Cancer Institute, Professor Zhang Bing of Baylor College of Medicine, Professor Ding Li of the Institute of Genetics of the University of Washington, and Wang of the Icahn School of Medicine at Mount Sinai, USA.
Supported by Prof.
Pei and Prof.
Daniel Figeys from the University of Ottawa, Canada
.

This research is also a major scientific research output based on the Public Technology Center of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences
.

　　Figure.
Link to the paper on proteomic analysis of intrahepatic cholangiocarcinoma: https://doi.
org/10.
1016/j.
ccell.
2021.
12.
006