RT Journal Article
SR Electronic
T1 Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 2019
OP 2031
DO 10.1136/gutjnl-2019-318912
VO 68
IS 11
A1 Zhang, Qi
A1 Lou, Yu
A1 Yang, Jiaqi
A1 Wang, Junli
A1 Feng, Jie
A1 Zhao, Yali
A1 Wang, Lin
A1 Huang, Xing
A1 Fu, Qihan
A1 Ye, Mao
A1 Zhang, Xiaozhen
A1 Chen, Yiwen
A1 Ma, Ce
A1 Ge, Hongbin
A1 Wang, Jianing
A1 Wu, Jiangchao
A1 Wei, Tao
A1 Chen, Qi
A1 Wu, Junqing
A1 Yu, Chengxuan
A1 Xiao, Yanyu
A1 Feng, Xinhua
A1 Guo, Guoji
A1 Liang, Tingbo
A1 Bai, Xueli
YR 2019
UL http://gut.bmj.com/content/68/11/2019.abstract
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.