Sixty-five gene-based risk score classifier predicts overall survival in hepatocellular carcinoma

Abstract

Clinical application of the prognostic gene expression signature has been delayed due to the large number of genes and complexity of prediction algorithms. In the current study we aimed to develop an easy-to-use risk score with a limited number of genes that can robustly predict prognosis of patients with hepatocellular carcinoma (HCC). The risk score was developed using Cox coefficient values of 65 genes in the training set (n = 139) and its robustness was validated in test sets (n = 292). The risk score was a highly significant predictor of overall survival (OS) in the first test cohort (P = 5.6 × 10(-5), n = 100) and the second test cohort (P = 5.0 × 10(-5) , n = 192). In multivariate analysis, the risk score was a significant risk factor among clinical variables examined together (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = 0.001 for OS).

Conclusion: The risk score classifier we have developed can identify two clinically distinct HCC subtypes at early and late stages of the disease in a simple and highly reproducible manner across multiple datasets.

Figure 1. Stratification of HCC patients in NCI cohort with 65-gene risk score

(A) Venn diagram of gene lists from two independently generated prognostic expression signatures. (B) Risk scores in the NCI cohort. Each bar represents the risk score for an individual patient. (C) Kaplan-Meier plots of the two subgroups in the NCI cohort stratified by risk score. (D) Kaplan-Meier plots of the two subgroups in the NCI cohort stratified by NCI proliferation signature. (E) Kaplan-Meier plots of the two subgroups in the NCI cohort stratified by SNU recurrence signature. Percentages in parenthesis indicate recurrence rate in each subgroup. OS, overall survival.

Figure 2. Overall survival of HCC patients stratified by risk score in the Korean and LCI HCC cohorts

HCC patients in the Korean cohort (A) and LCI cohort (B) were stratified by 65-gene risk score. OS, overall survival.

Figure 3. Comparison of ROC curves of clinical variables and risk score in validation cohorts

Clinical variables and 65-gene risk score were applied to patients in pooled validation cohorts and their prognostic significance was estimated by AUC from ROC analysis for 3-year OS. AUC: area under curve, CI: 95% confident internal of AUC. TS: tumor size, VI: vasculature invasion. RS: risk score, AFP:alpha-feto protein

Figure 4. Kaplan–Meier plots of OS of HCC patients stratified by BCLC stages and risk score

Patients were stratified by BCLC stage (A) or risk score (B and C). P-values were obtained from the log-rank test.