Cancer Cell Shanghai Institute of Drug Research and Zhou Hu's research team collaborated to draw a panoramic view of the multi-omics molecular characteristics of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (intrahepatic cholangiocarcinoma, iCCA) is the second most common primary liver malignant tumor.
The current surgical resection rate is low and there is a lack of effective targeted/immunotherapy options
.
Intrahepatic cholangiocarcinoma has a highly heterogeneous genome mutation and tumor microenvironment, which may mediate its high aggressiveness and poor prognosis
.
Therefore, there is an urgent need to conduct a "bird's eye view" study of iCCA, draw its precise molecular map, and provide a theoretical basis for systematic understanding of the heterogeneity of intrahepatic cholangiocarcinoma and individualized treatment
.

On December 30, 2021, Cancer Cell magazine published an online title of the collaboration between Researcher Zhou Hu from Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Academician Fan Jia and Professor Gao Qiang of Zhongshan Hospital Affiliated to Fudan University, and Researcher Gao Daming from the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences "Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma"
.
The study carried out protein genomics analysis on the tumor tissues of 262 iCCA patients.
By integrating multi-dimensional data such as genome, transcriptome, proteome, and phosphorylated proteome, the genesis and development mechanism, molecular classification, and molecular classification of intrahepatic cholangiocarcinoma were analyzed.
Prognostic monitoring and personalized treatment strategies provide new ideas
.

Researchers first analyzed the effects of major driving mutations in intrahepatic cholangiocarcinoma such as TP53, KRAS, FGFR2, IDH1/2, and BAP1 on the proteome and phosphorylated proteome
.
The study found that there are specific aflatoxin mutation fingerprints in Chinese population samples, which are significantly related to high tumor mutation burden and high NK cell infiltration
.
The fusion and mutation of FGFR2 may promote the development of iCCA by activating the Rho GTPase pathway.
Some of its fusion protein-derived peptides have strong immunogenicity and are potential immune antigen targets
.
Subsequently, the joint team further analyzed the cis and trans regulatory effects of chromatin copy number variation in intrahepatic cholangiocarcinoma on mRNA and protein
.
Researchers divide iCCA patients into four subtypes: inflammation (S1), mesenchyme (S2), metabolism (S3), and differentiation (S4) based on proteomic data.
The four subtypes have differentiated clinical features, mutation profiles, and Pathway enrichment and immune characteristic distribution, and there are significant prognostic differences
.
Through dimensionality reduction analysis, the team found a marker that can specifically distinguish the four subtypes, and verified the possibility of its use in clinical sample typing
.
In the end, researchers determined that HKDCl and SLC16A3 are biomarkers related to the prognosis of iCCA
.

　　This research is carried out under the framework of high quality standards of the International Cancer Proteogenome Consortium (ICPC) and the International Clinical Proteomic Tumor Analysis Consortium (CPTAC) for intrahepatic cholangiocarcinoma.
Cohort of protein genomics analysis
.
On the one hand, the research fully revealed the impact of gene mutations and chromatin variations in intrahepatic cholangiocarcinoma on the proteome and phosphorylated proteome.
Four molecular types and biomarkers were proposed from the proteome level to explore tumor heterogeneity.
Sexuality and the realization of individualized treatment provide clues; on the other hand, the high-quality big data generated by the research will continue to provide support for basic and clinical research on intrahepatic cholangiocarcinoma
.

　　Dr.
Dong Liangqing, Zhongshan Hospital Affiliated to Fudan University, Lu Dayun, PhD candidate at Shanghai Institute of Materia Medica, Chen Ran, Ph.
D.
candidate at the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Lin Youpei, Ph.
D.
candidate at Zhongshan Hospital, Fudan University, Zhu Hongwen, Associate Researcher, Shanghai Institute of Materia Medica, Zhang Dr.
Zhou and Dr.
Cai Shangli are the co-first authors of this article
.
Academician Fan Jia, Researcher Zhou Hu, Researcher Gao Daming and Professor Gao Qiang are the co-corresponding authors of this article
.
In addition, the research was supported by He Fuchu, Academician of the National Center for Protein Science (Beijing), Dr.
Henry Rodriguez of the National Cancer Institute, Professor Zhang Bing of the 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.
The strong support of Professor Pei and Professor Daniel Figeys of the University of Ottawa, Canada
.
The research is also a major scientific research output based on the Public Technology Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences
.

　　Full text link: https://doi.
org/10.
1016/j.
ccell.
2021.
12.
006

　　

Figure.
Protein genomics analysis of intrahepatic cholangiocarcinoma

(Contribution department: Zhou Hu's research group)