Comprehensive analysis of miRNA sequencing profiles identifies novel deregulated and prognostic biomarkers in hepatocellular carcinoma
Abstract Background: Liver cancer is the fourth most common cause of cancer-related death and rank sixth in terms of incident cases. We aim to identify a set of miRNAs and a miRNA-based signature related to tumorigenesis and prognosis in patients with hepatocellular carcinoma (HCC). Methods: We analyzed the miRNA sequencing profiles of 373 HCC patients downloaded from The Cancer Genome Atlas LIHC program. The isoform quantification profiles were transformed into 5p and 3p mature miRNA names. Differentially expressed (DE) miRNAs between tumor and adjacent normal tissues were identified by Wald test based on the negative binomial distribution. Prognostic miRNAs associated with overall survival were confirmed by multivariate Cox proportional hazards models. The miRNA-based signatures were obtained from the linear predictors of cox regression, and the prognostic performance was compared by Harrel’s C-index and revealed by the restricted mean survival (RMS) curve. Results: The selected twelve DE miRNAs showed a good performance to classify tumor tissues from normal tissues. Meanwhile, a miRNA-based prognostic signature of eight mature miRNAs was constructed, which significantly stratified patients into high- vs low-risk groups in terms of overall survival (hazard ratio, 4.11; 95% CI, 2.71-6.24; P<0.001). When integrated with clinical information, the composite miRNA-clinical signature showed improved prognostic accuracy relative to the eight-miRNA signature alone. As we set the follow-up time at 5 years, the estimated RMST difference between low- and high-risk group stratified by miRNA index was 1.39 (95% CI: 0.95-1.83) months, which is lesser than the difference between miRNA-clinical risk groups (1.63, 95%CI: 1.20-2.06). Functional enrichment analysis indicated that the target mRNAs of selected miRNAs were mainly enriched in cancer-related pathways and vital cell biological processes. Conclusions: The proposed DE miRNAs and miRNA-clinical signature are promising biomarkers for discrimination and predicting overall survival respectively in HCC patients. These biomarkers may have significant relevance for development of new drug research and targeting therapies for HCC patients.