Identification and validation of a prognostic four-genes signature for hepatocellular carcinoma: integrated ceRNA network analysis

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, with a poor long-term prognosis worldwide. The functional deregulations of global transcriptome were associated with the genesis and development of HCC, but lacks systematic research and validation.MethodsA total of 519 postoperative HCC patients were included. We built an interactive and visual competing endogenous RNA network. The prognostic signature was established with the least absolute shrinkage and selection operator algorithm. Multivariate Cox regression analysis was used to screen for independent prognostic factors for HCC overall survival.ResultsIn the training set, we identified a four-gene signature (PBK, CBX2, CLSPN, and CPEB3) and effectively predicted the overall survival. The survival times of patients in the high-score group were worse than those in the low-score group (p = 0.0004), and death was also more likely in the high-score group (HR 2.444, p < 0.001). The results were validated in internal validation set (p = 0.0057) and two external validation cohorts (HR 2.467 and 2.6). The signature (AUCs of 1, 2, 3 years were 0.716, 0.726, 0.714, respectively) showed high prognostic accuracy in the complete TCGA cohort.ConclusionsIn conclusion, we successfully built a more extensive ceRNA network for HCC and then identified a four-gene-based signature, enabling prediction of the overall survival of patients with HCC.Electronic supplementary materialThe online version of this article (10.1007/s12072-019-09962-3) contains supplementary material, which is available to authorized users.

Prognostic four-gene signature for overall survival in patients with hepatocellular carcinoma

“…They used high-throughput sequencing data of mRNAs, lncRNAs, miRNAs of 374 HCC samples, and 50 normal samples from the Cancer Genome Atlas (TCGA, https ://porta l.gdc.cance r.gov/) and performed multivariate Cox regression analysis to identify independent factors for the prediction of overall survival (OS) of patients with HCC [2]. They confirmed their results by external validation cohorts from two independent centers [2].…”

“…Although they found 1071 differentially expressed lncR-NAs, including 1014 (94.67%) upregulated and 57 (5.32%) downregulated lncRNAs, only 162 (95.29%) upregulated and 8 (4.71%) downregulated differentially expressed miRNAs were observed [2]. Next, by performing functional enrichment and survival analyses of key ceRNAs, they identified 20 mRNAs, 1 miRNA (miR-137) and 14 lncRNAs were significantly associated with the OS of patients with HCC [2]. A LASSO regression model [3] was used to identify a predictive signature from a TCGA training set and four genes [PDZ-binding kinase (PBK), Chromobox 2 (CBX2), CLSPN, and cytoplasmic polyadenylation element-binding protein 3 (CPEB3)], associated with the OS of patients with HCC, were identified [2].…”

“…Among the TCGA set, they identified a total of 1993 differentially expressed mRNAs, of which 1788 (89.71%) were upregulated and 205 (10.29%) were downregulated mRNAs [2]. Although they found 1071 differentially expressed lncR-NAs, including 1014 (94.67%) upregulated and 57 (5.32%) downregulated lncRNAs, only 162 (95.29%) upregulated and 8 (4.71%) downregulated differentially expressed miRNAs were observed [2].…”

“…In this issue, Yan et al performed integrated competing endogenous RNA (ceRNA) network analysis and established the prognostic signature with the least absolute shrinkage and selection operator algorithm [2]. They used high-throughput sequencing data of mRNAs, lncRNAs, miRNAs of 374 HCC samples, and 50 normal samples from the Cancer Genome Atlas (TCGA, https ://porta l.gdc.cance r.gov/) and performed multivariate Cox regression analysis to identify independent factors for the prediction of overall survival (OS) of patients with HCC [2]. They confirmed their results by external validation cohorts from two independent centers [2].…”

“…Among the TCGA set, they identified a total of 1993 differentially expressed mRNAs, of which 1788 (89.71%) were upregulated and 205 (10.29%) were downregulated mRNAs [2]. Although they found 1071 differentially expressed lncR-NAs, including 1014 (94.67%) upregulated and 57 (5.32%) downregulated lncRNAs, only 162 (95.29%) upregulated and 8 (4.71%) downregulated differentially expressed miRNAs were observed [2]. Next, by performing functional enrichment and survival analyses of key ceRNAs, they identified 20 mRNAs, 1 miRNA (miR-137) and 14 lncRNAs were significantly associated with the OS of patients with HCC [2].…”