Integrative analysis of miRNA and mRNA expression profiles reveals a novel mRNA/miRNA signature to improve risk classification for patients with gastric cancer

摘要

Gastric cancer (GC) is one of the most common types of malignant cancer and is associated with poor prognosis. Although the prognosis of patients with GC is associated with grade, stage and lymph node metastases, these traditional clinical features are inadequate to predict the outcome of GC. Therefore, there has been an increased focus on identifying novel molecular biomarkers for early diagnosis and prognosis, in order to improve outcomes in GC. In the present study, an integrative analysis of microRNA (miRNA) expression profiles, mRNA expression profiles and clinical characteristics was performed in a large cohort of patients with GC in order to identify an integrative prognostic model for improving postoperative risk classification. An integrative mRNA/miRNA signature (IMMIS), comprised of three miRNAs and one mRNA, was identified from a large number of differentially expressed miRNAs and mRNAs using univariate and multivariate Cox regression analysis. The prognostic value of the IMMIS was validated in the discovery cohort, testing cohort and The Cancer Genome Atlas (TCGA) cohort. The present results suggested that the identified signature had a reliable predictive performance and could classify the patients into high- and low-risk groups with significantly different overall survival times. In the discovery cohort, the hazard ratio (HR) was 2.805 with a 95% CI=1.722–4.567 (P<0.001). The median overall survival time as 1.49 vs. 3.85 years. In the testing cohort, the HR was 1.625 with a 95% CI=1.004–2.638 (P=0.039) and the median overall survival time was 2.17 vs. 4.62 years. In the TCGA cohort, the HR was 2.139 with a 95% CI=1.519–3.012 (P<0.001) and the median overall survival time was 1.53 vs. 4.62 years. The IMMIS constituted a reliable independent prognostic factor compared with clinical covariates, including age, sex, grade and stage, as indicated by multivariate and stratified analyses. Furthermore, comparative analysis revealed that the predictive value of the IMMIS was superior to the mRNA-based signature alone. The present results suggested the potential value of the IMMIS as a promising novel biomarker for improving the clinical management of patients with GC.