Experts comment on Cancer Cell Fan Jia/Zhou Hu/Gao Daming/Gao Qiang to draw the multi-omics molecular feature panorama of intrahepatic cholangiocarcinoma

Comment | Researcher Jiang Ying, Academician He Fuchu (National Center for Protein Science (Beijing)) Editor | xi Intrahepatic cholangiocarcinoma is the second most common primary liver malignant tumor.
The current surgical resection rate is low and there is a lack of effective targeting/immunity Treatment plan [1]
.

A large number of studies have shown that intrahepatic cholangiocarcinoma has a highly heterogeneous genome mutation and tumor microenvironment, which may mediate its high aggressiveness and poor prognosis [2-7]
.

In recent years, multi-omics research strategies based on large clinical samples with proteome as the core have revealed the molecular characteristics and potential treatment strategies of multiple tumor types from a "bird's eye view" panoramic view
.

For example, the Fan Jia/Zhou Hu/Gao Daming team thoroughly analyzed the occurrence and development mechanism of liver cancer through protein genomics research, and provided new ideas and strategies for accurate classification and individualized treatment of liver cancer, curative effect monitoring and prognosis judgment ( For details, please refer to the BioArt report: Cell | Fan Jia/Zhou Hu/Gao Daming team collaborated on liver cancer protein genome research, fully revealing the development mechanism of liver cancer and new ideas for diagnosis and treatment) [8]; He Fuchu/Qian Xiaohong/Fan Jia cooperated to complete the early stage Hepatocellular carcinoma proteomics related research, and found a new target for early liver cancer treatment, sterol O-acyltransferase 1 (SOAT1) (see BioArt report for details: NatureChinese scientists found a new target for precise treatment of liver cancer-open protein A new era of precision medicine driven by omics) [9]
.

For intrahepatic cholangiocarcinoma, this multi-omics strategy can provide a theoretical basis for systematic understanding of tumor heterogeneity and individualized treatment by drawing a more precise molecular map
.

On December 30, 2021, Fan Jia, Academician of Zhongshan Hospital Affiliated to Fudan University, Researcher Zhou Hu from Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Researcher Gao Daming from the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, and Professor Gao Qiang's research group from Zhongshan Hospital Affiliated to Fudan University collaborated in Cancer A research paper titled Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma was published on Cell.
Based on the genome, transcriptome, proteome, and phosphorylated proteome data from 262 cases of intrahepatic cholangiocarcinoma patients The multi-dimensional molecular atlas of intrahepatic cholangiocarcinoma provides new ideas for the occurrence and development of intrahepatic cholangiocarcinoma, molecular classification, prognostic monitoring and personalized treatment strategies
.

 In this study, the researchers collected the tumors and paracancerous tissues of 262 patients with intrahepatic cholangiocarcinoma from Zhongshan Hospital affiliated to Fudan University, and used the whole exome, transcriptome, proteome, phosphorylation group, and microbes.
Group and other multi-omics describe the multi-dimensional characteristics of intrahepatic cholangiocarcinoma
.

Studies have found that mutations (fusions) of TP53, KRAS, FGFR2, IDH1/2, and BAP1 are the main driving gene mutations of intrahepatic cholangiocarcinoma
.

In addition, the study found that there are a large number of aflatoxin mutation fingerprints in the intrahepatic cholangiocarcinoma samples of the Chinese population, and these carcinogen fingerprints are significantly related to higher tumor mutation burden and high NK cell infiltration
.

The researchers further analyzed the multi-omics characteristics of chromatin copy number variation in intrahepatic cholangiocarcinoma and found that loss of tumor suppressor genes (such as ARID1A, MAP2K4, MLH1) and oncogene amplification (such as STK19, HIST1H1E, MCL1, MDM4) are the main Event, and nearly 40% of intrahepatic cholangiocarcinomas have genetic changes that can be targeted by drugs
.

Copy number variation has cis-regulatory and trans-regulatory effects on mRNA and protein expression.
In particular, the loss of 14q chromosome causes down-regulation of proteasome-related protein expression through cis-effects, and further causes spliceosome, mismatch repair, and mismatch repair through trans-regulatory effects.
DNA replication and increased expression of cell cycle-related proteins may be an important mechanism for the occurrence and development of intrahepatic cholangiocarcinoma
.

 The study also found that TP53, KRAS, IDH1/2, BAP1, and FGFR2 mutations are independent driving events in intrahepatic cholangiocarcinoma, and the fine characteristics of the protein genome affected by these mutations have been studied one by one
.

Specifically, TP53 mutations are related to the activation of cell cycle, drug metabolism, phagosome and carbon metabolism pathways, while KRAS mutations lead to the up-regulation of inflammation-infection and ECM-focal adhesion pathway related proteins
.

BAP1 and IDH1/2 mutant tumors express high levels of bile acid secretion and ECM pathways, respectively, and immune inflammation and MAPK pathways are activated in IDH1/2 mutant tumors
.

It is worth noting that there are 10 intrahepatic cholangiocarcinoma samples with TP53 and KRAS co-mutations and the worst prognosis.
Omics data shows that cell adhesion-related molecules (such as ITGB6, CDH3, CLDN18) are expressed most in this type of tumor.
Mutations may promote metastasis through the integrin-FAK/SRC pathway
.

Importantly, the study also found that 10% of intrahepatic cholangiocarcinoma samples detected FGFR2 with a fusion-based mutation mode and point mutations as a secondary mutation.
It was also found that FGFR2 fusion protein changed its own activation mode and downstream phosphorylation transmission pathways, and was partially fused Protein-derived peptides have strong immunogenicity to cause specific T cell population activation and expansion, and can be used as potential neoantigen immunotherapy targets
.

 Finally, the researchers explored the molecular classification of intrahepatic cholangiocarcinoma with the proteome as the core, and found that it can be divided into four subtypes: inflammation (S1), mesenchyme (S2), metabolism (S3), and differentiation (S4)
.

The four subtypes have differentiated clinical features, mutation profiles, pathway enrichment, and immune microenvironment.
S1 is mostly CA19-9 elevated, tumor necrosis, intrahepatic metastasis, KRAS mutations and neutrophil aggregation; S2 has more High lymph node metastasis, TP53 mutation and fibroblast enrichment, S3 is characterized by HBV infection, while S4 is mainly enriched in patients with low CA19-9 and less metastasis
.

On the whole, S1 has the worst prognosis, while S4 has the best prognosis.
The four subtypes show protein subtype-specific drug sensitivity characteristics
.

The researchers further used supervised analysis to identify prognostic markers and found that HKDC1 and SLC16A3 have the most significant positive and negative correlations with patient survival outcomes.
Further molecular biology experiments have shown that HDKC1 and SLC16A3 participate in the regulation of tumor metabolism through glycolysis
.

In summary, the study identified four molecular subtypes of intrahepatic cholangiocarcinoma at the proteomic level: inflammation (S1), mesenchyme (S2), metabolism (S3), and differentiation (S4).
These subtypes are in the genome, The immune microenvironment, drug response, prognosis and other aspects have unique characteristics, and the five main driving genes of intrahepatic cholangiocarcinoma and the targeted potential therapeutic targets (TP53, KRAS, FGFR2, IDH1/2, BAP1) are clearly defined.
Revealed the signal characteristics related to mutations, clarified that FGFR2 fusion is a master clone mutation and its derived peptides can be used as immune antigen targets, and found that HKDC1 and SLC16A3 are important prognostic indicators for intrahepatic cholangiocarcinoma
.

The research is a protein genomics research aimed at intrahepatic cholangiocarcinoma under the framework of the high quality standards of the International Cancer Proteomic Consortium (ICPC) and the International Clinical Tumor Proteomics Analysis Consortium (CPTAC).
On the one hand, it fully reveals the intrahepatic The multi-group classification and new markers of cholangiocarcinoma have taken an important step towards exploring tumor heterogeneity and realizing individualized treatment; on the other hand, the high-quality big data generated by this research will continue to provide the basis for intrahepatic cholangiocarcinoma.
Clinical investigators provide support
.

 Academician Fan Jia of Zhongshan Hospital Affiliated to Fudan University, Researcher Zhou Hu of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Researcher Gao Daming of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, and Professor Gao Qiang of Zhongshan Hospital Affiliated to Fudan University are the co-corresponding authors of this article
.

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

This work 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 Daniel Figeys of the University of Ottawa, Canada, Professor Li Ding of the University of Washington Institute of Genetics, Mount Sinai, USA Strong support from Professor Pei Wang from Icahn School of Medicine
.

                                                                        Experts comment on researcher Jiang Ying and Academician He Fuchu (National Center for Protein Science (Beijing)) "Proteomics-driven precision medicine" new paradigm has made breakthrough progress: intrahepatic cholangiocarcinoma is second only to hepatocellular carcinoma in incidence Primary liver malignant tumor
.

Previous studies focused on genome and transcriptome detection and molecular typing.
The team of Academician Fan Jia/Researcher Zhou Hu/Researcher Gao Daming/Professor Gao Qiang’s team used proteomics as the core multi-omics research strategy, which was the first in the Chinese population cohort.
, Drew a multi-dimensional molecular map of intrahepatic cholangiocarcinoma, and provided new ideas for the occurrence and development of intrahepatic cholangiocarcinoma, molecular classification, prognostic monitoring and personalized treatment strategies
.

The Human Genome Project (HGP) was led by American scientists in 1985.
Scientists from many countries have measured more than 3 billion base sequences of the human genome.
It has changed the understanding of human life and disease and has become the driving force for the development of precision medicine.
Society has brought huge economic benefits
.

Typical representatives are the Human Genome Haplotype Map (HapMap) project, the Tumor Genome Atlas (TCGA) project, and the American Clinical Proteomic Tumor Analysis Project (CPTAC) [10-13], which are inherited from HGP
.

Protein is the executor of life activities and is closely related to the occurrence, development and outcome of health and disease
.

In recent years, with the rapid development of the depth and throughput of proteomics sequencing, China has organized the implementation of the "China Human Proteomics Project" and has taken the lead in establishing a new paradigm of "Proteomics-Driven Precision Medicine (PDPM)", which is giving rise to precision medicine research.
Significant impact [14,15,9]
.

The author believes that the work of this article further interprets the advantages of PDPM from the following three highlights: 1) Establish a molecular classification of intrahepatic cholangiocarcinoma with the proteome as the core
.

In the past, many molecular types of intrahepatic cholangiocarcinoma have been established based on the detection of genome and transcriptome [16-19]
.

In this study, although the author also collected genomics and transcriptomics data, the core prognostic-related molecular typing findings were obtained by relying on proteomic data
.

It means that the proteome is the real representative of the organ-specific and real-time phenotype of the life process of the biological system.
The molecular characteristics of proteomics and the established molecular typing more accurately describe the characteristics of the disease process, and the type-specific marker protein will Become an important therapeutic target
.

2) Discovery of new antigen peptides of fusion proteins and new targets for immunotherapy based on immunopeptomics technology
.

Genes are the carriers of genetic information.
Genes must be transcribed and translated into proteins in order to perform various functions of life activities.
Proteins are the main target of drug therapy, and protein products of mutant genes are excellent targets for tumor treatment, and tumor renewal The detection and quantification of antigens has always been the focus of the international cancer clinical research and clinical proteomics circles
.

This study found that 10% of the samples of the Chinese population with intrahepatic cholangiocarcinoma detected a mutation pattern of FGFR2 mainly fusion and supplemented by point mutations
.

However, the author did not stop there.
Using mass spectrometry flow cytometry (CyTOF) and immunopeptideomics technology to further verify that the fusion protein-derived peptides have strong immunogenicity and cause specific T cell population activation and expansion, which can be used as potential Neoantigen immunotherapy target
.

This important discovery marks an important step forward for proteomics technology in facing clinical needs
.

3) Based on proteomic data, discover important prognostic markers for intrahepatic cholangiocarcinoma
.

The omics research of large cohorts of clinical samples is extremely challenging.
It is inseparable from clinical scientists’ systematic management of sample enrollment, quality control and prognosis tracking, qualitative and quantitative omics technology, integrated analysis of biological big data, and the discovery of biomarkers.
Jointly tackling key issues with transformation
.

I am gratified that more and more clinical scientists and proteomists have joined forces to establish a database of clinical samples from large cohorts such as tumors, and discovered a number of prognostic markers and candidate targets with important transformational prospects
.

The research in this article once again proves that these candidate proteins identified from the proteome changes not only have a powerful role in identifying patients with poor prognosis of intrahepatic cholangiocarcinoma, but also enable these patients to receive further targeted therapy
.

This article is another masterpiece of the team of Academician Fan Jia/Researcher Zhou Hu/Researcher Gao Daming/Professor Gao Qiang after the publication of the multi-omics study of hepatocellular carcinoma [8]
.

It is not difficult to see that precision medicine driven by proteomics has made important breakthroughs in the large-scale discovery of diagnostic markers (groups) and therapeutic targets (groups) of major diseases, which will further expand China's advantages in the field of precision medicine.
, To promote the innovative development of China's biomedical industry
.

Original link: https://doi.
org/10.
1016/j.
ccell.
2021.
12.
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Instructions for reprinting [Non-original article] Copyright of this article Owned by the author of the article, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, offenders must be investigatedIntegrative Proteomic Characterization of Human Lung Adenocarcinoma.
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Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma.
Cancer Cell 2017, 32: 57-70.
19.
Xue R, et al.
Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes.
Cancer Cell 2019, 35: 932-947.
Reprinting notice [Non-original article] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, and it is prohibited without permission Reprinted, the author has all legal rights, offenders must be investigatedIntegrative Proteomic Characterization of Human Lung Adenocarcinoma.
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18.
Chaisaingmongkol J, et al.
Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma.
Cancer Cell 2017, 32: 57-70.
19.
Xue R, et al.
Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes.
Cancer Cell 2019, 35: 932-947.
Reprinting notice [Non-original article] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, and it is prohibited without permission Reprinted, the author has all legal rights, offenders must be investigated17.
Jusakul A, et al.
Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.
Cancer discovery 2017, 7: 1116-1135.
18.
Chaisaingmongkol J, et al.
Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma.
Cancer Cell 2017 , 32: 57-70.
19.
Xue R, et al.
Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes.
Cancer Cell 2019, 35: 932-947.
Notes for reprinting [Non-original article] The copyright of this article belongs to the author of the article All, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, offenders must be investigated17.
Jusakul A, et al.
Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.
Cancer discovery 2017, 7: 1116-1135.
18.
Chaisaingmongkol J, et al.
Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma.
Cancer Cell 2017 , 32: 57-70.
19.
Xue R, et al.
Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes.
Cancer Cell 2019, 35: 932-947.
Notes for reprinting [Non-original article] The copyright of this article belongs to the author of the article All, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, offenders must be investigatedGenomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes.
Cancer Cell 2019, 35: 932-947.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all statutory rights and offenders must be investigatedGenomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes.
Cancer Cell 2019, 35: 932-947.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all statutory rights and offenders must be investigated
.