Comprehensive Analysis of BAP1 Somatic Mutation in Clear Cell Renal Cell Carcinoma to Explore Potential Mechanisms in Silico

Shengming Jin^1,2*, Junlong Wu^1,2*, Yao Zhu^1,2, Weijie Gu^1,2, Fangning Wan^1,2, Wenjun Xiao^1,2, Bo Dai^1,2, Hailiang Zhang^1,2, Guohai Shi^1,2, Yijun Shen^1,2, Yiping Zhu^1,2✉, Dingwei Ye^1,2✉

1. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
*These authors contributed equally to this work.

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Citation:
Jin S, Wu J, Zhu Y, Gu W, Wan F, Xiao W, Dai B, Zhang H, Shi G, Shen Y, Zhu Y, Ye D. Comprehensive Analysis of BAP1 Somatic Mutation in Clear Cell Renal Cell Carcinoma to Explore Potential Mechanisms in Silico. J Cancer 2018; 9(22):4108-4116. doi:10.7150/jca.27281. Available from https://www.jcancer.org/v09p4108.htm

Abstract

Purpose: Aim of this study was to comprehensively analyze BRCA1-associated protein-1 (BAP1) somatic mutation in clear cell renal cell carcinoma (ccRCC) and explore potential therapeutic pathways and molecules.

Patients and methods: In this study, we analyzed 445 ccRCC cases from The Cancer Genome Atlas (TCGA). Comprehensive analysis including survival, transcriptome and methylation between BAP1 mutated and wild-type cases was performed using bioinformatics tools in silico. Pathways and molecules related to BAP1 mutation were analyzed using Database for Annotation, Visualization and Integrated Discovery (DAVID) and protein-protein interaction (PPI) network.

Results: BAP1 mutated ccRCC patients had a worse overall survival (OS) and disease free survival (DFS) than BAP1 wild-type patients. We found 583 up-regulated and 1216 down-regulated different expressed genes (DEGs) in BAP1 mutated tumors. Up-regulated DEGs were enriched in molecular functions and biological processes like protein binding, protein transport and ubiquitin protein ligase binding. Down-regulated DEGs were enriched in pathways like Rap1 signaling pathway, Notch pathway and altered molecular functions like metal ion binding and ubiquitin-protein transferase activity. Furthermore, CAD, TSPO, CTNNB1 and MAPK3 were top hub genes selected using PPI network analysis. Finally, BAP1 mutation had a strong correlation with CpG island methylator phenotype (CIMP).

Conclusion: Our study provides a comprehensive understanding of BAP1 functional somatic mutation in ccRCC patients. Several hub genes like CAD and TSPO may become potential therapeutic targets.

Keywords: clear cell renal cell carcinoma, BAP1, mutation, bioinformatics