A <i>BAP1</i> Mutation-specific MicroRNA Signature Predicts Clinical Outcomes in Clear Cell Renal Cell Carcinoma Patients with Wild-type <i>BAP1</i>

Abstract

<b>Background:</b> Clear cell renal cell carcinoma (ccRCC) is the most prevalent histologic subtype of kidney cancers in adults, which could be divided into two distinct subgroups according to the <i>BRCA1 associated protein-1</i> (<i>BAP1</i>) mutation status. In the current study, we comprehensively analyzed the genome-wide microRNA (miRNA) expression profiles in ccRCC, with the aim to identify the differentially expressed miRNAs between <i>BAP1</i> mutant and wild-type tumors, and generate a <i>BAP1</i> mutation-specific miRNA signature for ccRCC patients with wild-type <i>BAP1</i>. <b>Methods:</b> The <i>BAP1</i> mutation status and miRNA profiles in <i>BAP1</i> mutant and wild-type tumors were analyzed. Subsequently, the association of the differentially expressed miRNAs with patient survival was examined, and a <i>BAP1</i> mutation-specific miRNA signature was generated and examined with Kaplan-Meier survival, univariate and multivariate Cox regression analyses. Finally, the bioinformatics methods were adopted for the target prediction of selected miRNAs and functional annotation analyses. <b>Results:</b> A total of 350 treatment-naïve primary ccRCC patients were selected from The Cancer Genome Atlas project, among which 35 (10.0%) subjects carried mutant <i>BAP1</i> and had a shorter overall survival (OS) time. Furthermore, 33 miRNAs were found to be differentially expressed between <i>BAP1</i> mutant and wild-type tumors, among which 11 (miR-149, miR-29b-2, miR-182, miR-183, miR-21, miR-365-2, miR-671, miR-365-1, miR-10b, miR-139, and miR-181a-2) were significantly associated with OS in ccRCC patients with wild-type <i>BAP1</i>. Finally, a <i>BAP1</i> mutation-specific miRNA signature consisting of 11 miRNAs was generated and validated as an independent prognostic parameter. <b>Conclusions:</b> In summary, our study identified a total of 33 miRNAs differentially expressed between <i>BAP1</i> mutant and wild-type tumors, and generated a <i>BAP1</i> mutation-specific miRNA signature including eleven miRNAs, which could serve as a novel prognostic biomarker for ccRCC patients with wild-type <i>BAP1</i>.