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Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma

Abstract

We sequenced whole exomes of ten clear cell renal cell carcinomas (ccRCCs) and performed a screen of 1,100 genes in 88 additional ccRCCs, from which we discovered 12 previously unidentified genes mutated at elevated frequencies in ccRCC. Notably, we detected frequent mutations in the ubiquitin-mediated proteolysis pathway (UMPP), and alterations in the UMPP were significantly associated with overexpression of HIF1α and HIF2α in the tumors (P = 0.01 and 0.04, respectively). Our findings highlight the potential contribution of UMPP to ccRCC tumorigenesis through the activation of the hypoxia regulatory network.

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Figure 1: Alterations in the UMPP are significantly associated with overexpression of HIF1α and HIF2α in ccRCC.

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Acknowledgements

This work was supported by the National Basic Research Program of China (973 program 2011CB809200), the National Natural Science Foundation of China (30725008, 30890032 and 30811130531), the Chinese 863 program (2006AA02A301, 2006AA02A302 and 2009AA022707), the Shenzhen Municipal Government of China (JC200903190767A, JC200903190772A, ZYC200903240076A, CXB200903110066A, ZYC200903240077A and ZYC200903240080A), the Promotion Program for Shenzhen Key Laboratory, Shenzhen, China (CXB200903090055A and CXB201005250016A) and the Biobank of Complex Diseases in Shenzhen (CXC201005260001A). This project was also funded by the Shenzhen municipal government and the local government of the Yantian District of Shenzhen.

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Authors

Contributions

Jun Wang, Z.C., Jian Wang, H.Y., S.L. and Y. Li managed the project. Xiaokun Zhao, C. Liang, F.Z., Z.L., X. Li, L.Z., J.C., Y.W., Z.J., S. Wu, Z.Z., R. Yang, W.Y., Y. Liu, B.J., J.L. and Q.F. prepared the samples. X. Zhang, X.H., Xiao Liu, R.W., L.L., Xia Zhao, H.P. and K.K. performed the sequencing. G.G., Y.G., S.G., A.T., Y.H., W.J., M.H., S. Wan, C.C., M.J., T.J. and R. Ye performed the bioinformatic analysis. S.Y., P.S., P.H., J. Zou, F.F., Xingwang Liu and H.W. performed the validation of somatic mutations. L.S. and C. Li performed the immunohistochemistry analysis. Z.L., J.X. and J. Zhu performed the methylation analysis. G.G., Y.G., Y. Li, A.T. and Y.H. wrote the manuscript, and Y.H., Y.G., G.G., Y. Li and X.S. revised the manuscript.

Corresponding authors

Correspondence to Huanming Yang, Zhiming Cai or Jun Wang.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figures 1–4 and Supplementary Tables 1, 2 and 6–9. (PDF 934 kb)

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Supplementary Table 5 (XLSX 52 kb)

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Guo, G., Gui, Y., Gao, S. et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet 44, 17–19 (2012). https://doi.org/10.1038/ng.1014

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