J Cancer 2017; 8(13):2643-2652. doi:10.7150/jca.20234

Research Paper

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

Yu-Zheng Ge1*, Lu-Wei Xu1*, Chang-Cheng Zhou1*, Tian-Ze Lu2, Wen-Tao Yao1, Ran Wu1, You-Cai Zhao3, Xiao Xu4, Zhi-Kai Hu1, Min Wang1, Xiao-Bing Yang3, Liu-Hua Zhou1, Bing Zhong5, Zheng Xu1, Wen-Cheng Li1, Jia-Geng Zhu1, Rui-Peng Jia1✉

1. Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
2. Department of Urology, Nantong Hospital of Traditional Chinese Medicine, 41 Jianshe Road, Nantong 226006, China.
3. Department of Pathology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
4. Department of Radiation Oncology, JiangSu Armed Police General Hospital, 8 Jiangdu South Road, Yangzhou 225003, China
5. Department of Urology, Huaian First People's Hospital, Nanjing Medical University, 6 Beijing West Road, Huaian 223300, China.
*These three authors (Yu-Zheng Ge, Lu-Wei Xu, and Chang-Cheng Zhou) contributed equally to this work.

Abstract

Background: 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 BRCA1 associated protein-1 (BAP1) 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 BAP1 mutant and wild-type tumors, and generate a BAP1 mutation-specific miRNA signature for ccRCC patients with wild-type BAP1.

Methods: The BAP1 mutation status and miRNA profiles in BAP1 mutant and wild-type tumors were analyzed. Subsequently, the association of the differentially expressed miRNAs with patient survival was examined, and a BAP1 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.

Results: 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 BAP1 and had a shorter overall survival (OS) time. Furthermore, 33 miRNAs were found to be differentially expressed between BAP1 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 BAP1. Finally, a BAP1 mutation-specific miRNA signature consisting of 11 miRNAs was generated and validated as an independent prognostic parameter.

Conclusions: In summary, our study identified a total of 33 miRNAs differentially expressed between BAP1 mutant and wild-type tumors, and generated a BAP1 mutation-specific miRNA signature including eleven miRNAs, which could serve as a novel prognostic biomarker for ccRCC patients with wild-type BAP1.

Keywords: clear cell renal cell carcinoma, BAP1, mutation, microRNA, prognosis

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How to cite this article:
Ge YZ, Xu LW, Zhou CC, Lu TZ, Yao WT, Wu R, Zhao YC, Xu X, Hu ZK, Wang M, Yang XB, Zhou LH, Zhong B, Xu Z, Li WC, Zhu JG, Jia RP. A BAP1 Mutation-specific MicroRNA Signature Predicts Clinical Outcomes in Clear Cell Renal Cell Carcinoma Patients with Wild-type BAP1. J Cancer 2017; 8(13):2643-2652. doi:10.7150/jca.20234. Available from http://www.jcancer.org/v08p2643.htm