Survival-Based Gene Expression Analysis of Chinese HCC Specimens Revealed Prognostic Biological Determinants Regulating Cancer Growth and Tumor Immunity

To identify important druggable targets and immunological determinants associated with the overall survival (OS) of hepatocellular carcinoma (HCC) patients, we interrogated 279 Chinese HCC samples, mostly in early stage, with the NanoString platform assessing the expression of 1,173 genes involved in cell-growth signaling pathways, cellular machineries and tumor immunity. A prognostic model was constructed using 17 genes with bootstrap-corrected C-index of 0.81 for the OS. Among the genes associated with worse OS, cell-growth related druggable targets CHK1 and EZH2 were selected for in vitro and in vivo tumor growth studies. HCC cell line clonogenic assays and mice xenograft models demonstrated that the combinatorial application of CHK1 inhibitor and EZH2 inhibitor resulted in significant suppression of HCC tumor growth. On the tumor immunity front, we discovered that genes enriched in regulating CD8+ T cells and activating NK cells contributed to prolonged OS. Our findings provide potential rationale for investigating combinatorial targeted therapies and immunotherapies in specific subsets of early-stage HCC with distinct gene expression characteristics. Funding: This work was supported by National Natural Science Fund of China (Grant numbers: No.81672330; No. 81871916; No. 81472218), Talent Development Program of Zhongshan Hospital (2015ZSYXGG), and by Genentech Inc., a member of the Roche Group. Declaration of Interest: Chun Sun, Bonnie Liu, Kwame Okrah, Xu Cao, Jian-Jun Guo, Shi-Jing Fu, Su-Chun Li, Hang-jun Dai, Mark R. Lackner, Astrid Kiermaier, Shih-Min A. Huang and Gang Cheng are employees of F. Hoffmann-La Roche/Genentech Inc. All other authors declare no conflict of interest. Ethical Approval: This study was approved, and the collection of written informed consent forms was waived, by the institutional review board of SZH under the condition that all samples were anonymized in this study.