Identification of an Immune-Related Prognostic Predictor in Hepatocellular Carcinoma

Lei Wu; Wen Quan; Qiong Luo; Ying Pan; Dongxu Peng; Guihai Zhang

doi:10.3389/fmolb.2020.567950

Identification of an Immune-Related Prognostic Predictor in Hepatocellular Carcinoma

Front Mol Biosci. 2020 Sep 24:7:567950. doi: 10.3389/fmolb.2020.567950. eCollection 2020.

Authors

Lei Wu¹, Wen Quan¹, Qiong Luo², Ying Pan¹, Dongxu Peng¹, Guihai Zhang¹

Affiliations

¹ Department of Oncology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China.
² Department of Oncology, Affiliated Zhuhai Hospital, Southern Medical University, Zhuhai, China.

Abstract

Liver hepatocellular carcinoma (LIHC) is the most prevalent primary cancer of the liver, and immune-related genes (IRGs) regulate its development. So far, there is still no precise biomarker that predicts response to immunotherapy in LIHC. Therefore, this research seeks to identify immunogenic prognostic biomarkers and explore potential predictors for the efficacy of anti-PD-1/PD-L1 therapies in LIHC. The clinical data and gene expression profiles of patients diagnosed with LIHC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Moreover, IRGs were obtained from the ImmPort database. We discovered 35 IRGs that were differentially expressed between LIHC tissues and corresponding normal tissues. Through univariate Cox regression analysis, eight prognostic differentially expressed IRGs (PDEIRGs) were identified. Further, three optimal PDEIRGs (BIRC5, LPA, and ROBO1) were identified and used to construct a prognostic risk signature of LIHC patients via multivariate Cox regression analysis. The signature was validated by ROC curves. Subsequently, based on gene set enrichment analysis (GSEA) analysis, two out of the three optimal PDEIRGs (BIRC5 and LPA) were significantly enriched in the mismatch repair (MMR) pathway. Moreover, the two PDEIRGs (BIRC5 and LPA) were significantly correlated with the expression of genes related to mismatch repair (MLH1, MSH2, MSH6, and PMS2). Furthermore, correlations between the two PDEIRGs (BIRC5 and LPA) and immune checkpoints of cancer treatment (such as CTLA4, PD-1, and PD-L1) were demonstrated. Hyperprogressive disease (HPD) is a novel pattern of tumor progression which has a close relationship with immune checkpoint inhibitors (ICIs) utilization. MDM2 family amplification might promote the HPD phenomenon. Finally, we found a positive regulatory relationship between HPD related gene (MDM2) and BIRC5. Notably, MDM2 can either interact directly with BIRC5 or indirectly via downstream transcription factors of BIRC5. Overall, our study uncovered a novel 3-immune-related prognostic genes in LIHC.

Keywords: HPD; PD-1; PD-L1; hepatocellular carcinoma; immune.