Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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

References

  1. 1

    Rini, B.I., Campbell, S.C. & Escudier, B. Lancet 373, 1119–1132 (2009).

    CAS  Article  Google Scholar 

  2. 2

    van Haaften, G. et al. Nat. Genet. 41, 521–523 (2009).

    CAS  Article  Google Scholar 

  3. 3

    Dalgliesh, G.L. et al. Nature 463, 360–363 (2010).

    CAS  Article  Google Scholar 

  4. 4

    Varela, I. et al. Nature 469, 539–542 (2011).

    CAS  Article  Google Scholar 

  5. 5

    Gui, Y. et al. Nat. Genet. 43, 875–878 (2011).

    CAS  Article  Google Scholar 

  6. 6

    Forbes, S.A. et al. Curr. Protoc. Hum. Genet. Chapter 10, Unit 10.11 (Wiley, 2008).

  7. 7

    Getz, G. et al. Science 317, 1500 (2007).

    CAS  Article  Google Scholar 

  8. 8

    Szymanska, K. et al. Cancer Lett. 293, 92–98 (2010).

    CAS  Article  Google Scholar 

  9. 9

    Banks, R.E. et al. Cancer Res. 66, 2000–2011 (2006).

    CAS  Article  Google Scholar 

  10. 10

    Harbour, J.W. et al. Science 330, 1410–1413 (2010).

    CAS  Article  Google Scholar 

  11. 11

    Lamb, R.F. et al. Nat. Cell Biol. 2, 281–287 (2000).

    CAS  Article  Google Scholar 

  12. 12

    Ding, L. et al. Nature 455, 1069–1075 (2008).

    CAS  Article  Google Scholar 

  13. 13

    Sonoda, I. et al. Cancer Res. 64, 3741–3747 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Linehan, W.M. et al. Annu. Rev. Med. 61, 329–343 (2010).

    CAS  Article  Google Scholar 

Download references

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.

Author information

Affiliations

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 or Zhiming Cai or Jun Wang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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

Supplementary Table 3

Supplementary Table 3 (XLSX 41 kb)

Supplementary Table 4

Supplementary Table 4 (XLSX 27 kb)

Supplementary Table 5

Supplementary Table 5 (XLSX 52 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing