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 gutjnl-2019-318912
DO 10.1136/gutjnl-2019-318912
A1 Qi Zhang
A1 Yu Lou
A1 Jiaqi Yang
A1 Junli Wang
A1 Jie Feng
A1 Yali Zhao
A1 Lin Wang
A1 Xing Huang
A1 Qihan Fu
A1 Mao Ye
A1 Xiaozhen Zhang
A1 Yiwen Chen
A1 Ce Ma
A1 Hongbin Ge
A1 Jianing Wang
A1 Jiangchao Wu
A1 Tao Wei
A1 Qi Chen
A1 Junqing Wu
A1 Chengxuan Yu
A1 Yanyu Xiao
A1 Xinhua Feng
A1 Guoji Guo
A1 Tingbo Liang
A1 Xueli Bai
YR 2019
UL http://gut.bmj.com/content/early/2019/06/12/gutjnl-2019-318912.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.