Construction and validation of a novel ten miRNA-pair based signature for the prognosis of clear cell renal cell carcinoma

Background: Clear cell renal cell carcinoma (ccRCC) is the most predominate pathological subtype of renal cell carcinoma, causing a recurrence or metastasis rate as high as 20% to 40% after operation, for which effective prognostic signature is urgently needed. Methods: The mRNA and miRNA profiles of ccRCC specimens were collected from the Cancer Genome Atlas. MiRNA-pair risk score (miPRS) for each miRNA pair was generated as a signature and validated by univariate and multivariate Cox proportional hazards regression analysis. Functional enrichment was performed, and im-mune cells infiltration, as well as tumor mutation burden (TMB), and immunophenoscore (IPS) were evaluated between high and low miPRS groups. Target gene-prediction and differentially expressed gene-analysis were performed based on databases of miRDB, miRTarBase, and TargetScan. Multivariate Cox proportional hazards regression analysis was adopted to establish the prognostic model and Kaplan-Meier survival analysis was performed. Findings: A novel 10 miRNA-pair based signature was established. Area under the time-dependent receiver operating curve proved the performance of the signature in the training, validation, and testing cohorts. Higher TMB, as well as the higher CTLA4-negative PD1-negative IPS, were discovered in high miPRS patients. A prognostic model was built based on miPRS (1 year-, 5 year-, 10 year-ROC-AUC=0.92, 0.84, 0.82, respectively). Interpretation: The model based on miPRS is a novel and valid tool for predicting the prognosis of ccRCC. Funding: This study was supported by research grants from the China National Natural Scientific Foundation (81903972, 82002018, and 82170752) and Shanghai Sailing Program (19YF1406700 and 20YF1406000).