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Spectrum of diverse genomic alterations define non–clear cell renal carcinoma subtypes

Nature Genetics volume 47, pages 13–21 (2015)Cite this article

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Abstract

To further understand the molecular distinctions between kidney cancer subtypes, we analyzed exome, transcriptome and copy number alteration data from 167 primary human tumors that included renal oncocytomas and non–clear cell renal cell carcinomas (nccRCCs), consisting of papillary (pRCC), chromophobe (chRCC) and translocation (tRCC) subtypes. We identified ten significantly mutated genes in pRCC, including MET, NF2, SLC5A3, PNKD and CPQ. MET mutations occurred in 15% (10/65) of pRCC samples and included previously unreported recurrent activating mutations. In chRCC, we found TP53, PTEN, FAAH2, PDHB, PDXDC1 and ZNF765 to be significantly mutated. Gene expression analysis identified a five-gene set that enabled the molecular classification of chRCC, renal oncocytoma and pRCC. Using RNA sequencing, we identified previously unreported gene fusions, including ACTG1-MITF fusion. Ectopic expression of the ACTG1-MITF fusion led to cellular transformation and induced the expression of downstream target genes. Finally, we observed upregulation of the anti-apoptotic factor BIRC7 in MiTF-high RCC tumors, suggesting a potential therapeutic role for BIRC7 inhibitors.

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Figure 1: Somatic mutations in nccRCC.
Figure 2: Significantly mutated genes in nccRCC.
Figure 3: RNA-seq–based classification of nccRCCs.
Figure 4: Proteins encoded by the CLTC-TFEB and MITF gene fusions.
Figure 5: ACTG1-MITF gene fusion promotes anchorage-independent growth.
Figure 6: Integrated analysis of alterations in key pathways in nccRCC subtypes.

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Acknowledgements

The authors would like to acknowledge the Genentech DNA Sequencing, Oligo and Bioinformatics groups for their help with the project. We thank D. Bhatt, R. Bourgon, Z. Zhang, C. Klijn, M. Brauer and L. Johnson for their support during the course of this project. We would like to acknowledge K. Mukhyala for assistance in gene annotation. This work was supported in part by grants 1R01CA175754 (US National Institutes of Health (NIH)) and RP130603 (CPRIT; Texas, USA) to J.B. and grant 5R01CA154475-04 (US NIH) to I.P. Sample collection was supported in part by grant 5P30CA142543 (US NIH). J.B. is a Virginia Murchison Linthicum Endowed Scholar in medical research.

Author information

Author notes

  1. Steffen Durinck, Eric W Stawiski, Andrea Pavía-Jiménez, Zora Modrusan and Payal Kapur: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Biology Department, Genentech, Inc, South San Francisco, California, USA

    Steffen Durinck, Eric W Stawiski, Zora Modrusan, Bijay S Jaiswal, Na Zhang, Thong T Nguyen, Kanika Bajaj Pahuja, Ying-Jiun Chen, Subhra Chaudhuri, Sherry Heldens, Marlena Jackson, Joseph Guillory, Karen Toy, Connie Ha, Corissa J Harris, Jeremy Stinson, Celina Sanchez Rivers, Vasantharajan Janakiraman, Bernard Chow & Somasekar Seshagiri

  2. Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA

    Steffen Durinck, Eric W Stawiski, Peter M Haverty, Julian S Gehring, Jens Reeder, Gregoire Pau & Thomas D Wu

  3. Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Andrea Pavía-Jiménez, Payal Kapur, Vanina Toffessi-Tcheuyap, Sadia Saleem, Samuel Peña-Llopis, Eboni Holloman, Haley M Hill, Lisa N Kinch, Nick V Grishin, Vitaly Margulis, Yair Lotan, Arthur Sagalowsky, Ivan Pedrosa & James Brugarolas

  4. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Andrea Pavía-Jiménez, Vanina Toffessi-Tcheuyap, Sadia Saleem, Samuel Peña-Llopis, Eboni Holloman, Haley M Hill & James Brugarolas

  5. Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Andrea Pavía-Jiménez, Vanina Toffessi-Tcheuyap, Samuel Peña-Llopis, Eboni Holloman, Haley M Hill & James Brugarolas

  6. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Payal Kapur

  7. Structural Biology Department, Genentech, Inc., South San Francisco, California, USA

    Weiru Wang

  8. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Lisa N Kinch & Nick V Grishin

  9. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Lisa N Kinch & Nick V Grishin

  10. Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Vitaly Margulis, Yair Lotan & Arthur Sagalowsky

  11. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Ivan Pedrosa

  12. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Ivan Pedrosa

  13. Molecular Oncology Department, Genentech, Inc., South San Francisco, California, USA

    Frederic J de Sauvage

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  1. Steffen Durinck
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Contributions

S.D. and E.W.S. performed the exome and RNA-seq analyses. T.T.N. performed the simulation analysis. E.W.S. and J.S.G. conducted the mutational signature studies. S.D. and P.M.H. performed copy number analysis. A.P.-J., V.T.-T., E.H., Z.M., H.M.H. and S.P.-L. were responsible for sample collection, annotation, processing, and DNA and RNA extraction. Z.M. oversaw the collection of the various data types. Z.M. and Y.-J.C. performed validation of the fusions. P.K. facilitated sample procurement, selected samples for DNA and RNA extraction, oversaw FISH analyses and served as the pathologist for the study. J.R. and G.P. processed the RNA-seq reads. T.D.W. provided support for gene fusion prediction. K.T., C.H., C.J.H. and C.S.R. prepared the sequencing libraries. N.Z., K.B.P., S.C. and B.S.J. performed biological validation studies. S. Saleem collected information about the cases. V.M., Y.L., A.S. and I.P. facilitated sample procurement. L.N.K. and N.V.G. performed in silico analyses. J.G., V.J. and J.S. collected sequencing data. J.G. performed mutation validation. B.C. analyzed targeted capture data. S.H. and M.J. performed Sanger sequencing to validate indels. W.W. predicted the structural consequences of MET mutations. F.J.d.S. provided organizational support. J.B. and S. Seshagiri conceived the study and designed the experiments. E.W.S., S.D., Z.M., P.K., J.B. and S. Seshagiri wrote the manuscript, which was reviewed and edited by the other coauthors.

Corresponding authors

Correspondence to James Brugarolas or Somasekar Seshagiri.

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Competing interests

All Genentech-affiliated authors (S.D., E.W.S., Z.M., B.S.J., N.Z., T.T.N., K.B.P., Y.-J.C., S.C., S.H., M.J., J.G., K.T., C.H., C.J.H., J.S., C.S.R., V.J., W.W., P.M.H., B.C., J.S.G., J.R., G.P., T.D.W., F.J.d.S. and S. Seshagiri) hold Roche shares.

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Durinck, S., Stawiski, E., Pavía-Jiménez, A. et al. Spectrum of diverse genomic alterations define non–clear cell renal carcinoma subtypes. Nat Genet 47, 13–21 (2015). https://doi.org/10.1038/ng.3146

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