PT  - JOURNAL ARTICLE
AU  - Zhang, Qi
AU  - Lou, Yu
AU  - Yang, Jiaqi
AU  - Wang, Junli
AU  - Feng, Jie
AU  - Zhao, Yali
AU  - Wang, Lin
AU  - Huang, Xing
AU  - Fu, Qihan
AU  - Ye, Mao
AU  - Zhang, Xiaozhen
AU  - Chen, Yiwen
AU  - Ma, Ce
AU  - Ge, Hongbin
AU  - Wang, Jianing
AU  - Wu, Jiangchao
AU  - Wei, Tao
AU  - Chen, Qi
AU  - Wu, Junqing
AU  - Yu, Chengxuan
AU  - Xiao, Yanyu
AU  - Feng, Xinhua
AU  - Guo, Guoji
AU  - Liang, Tingbo
AU  - Bai, Xueli
TI  - Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas
AID  - 10.1136/gutjnl-2019-318912
DP  - 2019 Nov 01
TA  - Gut
PG  - 2019--2031
VI  - 68
IP  - 11
4099  - http://gut.bmj.com/content/68/11/2019.short
4100  - http://gut.bmj.com/content/68/11/2019.full
SO  - Gut2019 Nov 01; 68
AB  - Objective Hepatocellular carcinoma (HCC) is heterogeneous, especially in multifocal tumours, which decreases the efficacy of clinical treatments. Understanding tumour heterogeneity is critical when developing novel treatment strategies. However, a comprehensive investigation of tumour heterogeneity in HCC is lacking, and the available evidence regarding tumour heterogeneity has not led to improvements in clinical practice.Design We harvested 42 samples from eight HCC patients and evaluated tumour heterogeneity using whole-exome sequencing, RNA sequencing, mass spectrometry-based proteomics and metabolomics, cytometry by time-of-flight, and single-cell analysis. Immunohistochemistry and quantitative polymerase chain reactions were performed to confirm the expression levels of genes. Three independent cohorts were further used to validate the findings.Results Tumour heterogeneity is considerable with regard to the genomes, transcriptomes, proteomes, and metabolomes of lesions and tumours. The immune status of the HCC microenvironment was relatively less heterogenous. Targeting local immunity could be a suitable intervention with balanced precision and practicability. By clustering immune cells in the HCC microenvironment, we identified three distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features. We further revealed the specific metabolic features and cytokine/chemokine expression levels of the different subtypes. Determining the expression levels of CD45 and Foxp3 using immunohistochemistry facilitated the correct classification of HCC patients and the prediction of their prognosis.Conclusion There is comprehensive intratumoral and intertumoral heterogeneity in all dimensions of HCC. Based on the results, we propose a novel immunophenotypic classification of HCCs that facilitates prognostic prediction and may support decision making with regard to the choice of therapy.