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BAP1 loss defines a new class of renal cell carcinoma

Nature Genetics volume 44, pages 751–759 (2012)Cite this article

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An Erratum to this article was published on 29 August 2012

This article has been updated

Abstract

The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10−5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.

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Figure 1: Integrative mutation and DNA copy-number analyses in a tumor and tumorgraft from the index subject.
Figure 2: BAP1 is a tumor suppressor in ccRCC.
Figure 3: HCF-1–dependent suppression of cell proliferation by BAP1.
Figure 4: BAP1 binds to and elutes with HCF-1 in tumorgrafts.
Figure 5: Loss of BAP1 and PBRM1 form the basis of a molecular genetic classification system for ccRCCs.

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Change history

  • 21 June 2012

    In the version of this article initially published, the P value given in the abstract for the anticorrelation between BAP1 and PBRM1 mutations was given incorrectly as 9 × 10−6 instead of 3 × 10−5. The definition of mutant allele ratios (MARs) in the text on p. 1 of the PDF has been corrected. The titles and legends of Figure 1 and Table 1 incorrectly stated that data were presented from multiple tumors and tumorgrafts; these have been corrected to reflect that data came from one index subject. The title of Figure 2 originally referred to mutated residues; this has now been corrected to state that alterations in BAP1 are shown. On p. 7 of the PDF the text has been corrected to state that "a few tumors had loss of both BAP1 and PBRM," whereas the text originally incorrectly cited somatic mutations in both genes. The errors have been corrected in the HTML and PDF versions of the article.

  • 29 August 2012

    An Erratum to this paper has been published: https://doi.org/10.1038/ng0912-1072b

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Acknowledgements

We recognize the individuals who participated in the study and who donated samples. We thank O. Sepulveda, A. Husain and A. Yadlapalli for technical support, S. Cohenour and D. Sheppard for assistance with contracts and regulatory considerations, Y. Machida (Mayo Clinic) for providing plasmids, B. Grossman (MD Anderson Cancer Center) for providing the UMRC cells, C. Camacho and N. Tomimatsu for irradiating cells, and the staff of the UT Southwestern Tissue Resource. This work was supported by a fellowship of excellence from Generalitat Valenciana (BPOSTDOC06/004 to S.P.-L.) and by the following awards to J.B.: a grant from the Cancer Prevention and Research Institute of Texas (RP101075), a Clinical Scientist Development Award from the Doris Duke Charitable Foundation, an American Cancer Society Research Scholar grant (115739) and a grant from the US. National Institutes of Health (RO1 CA129387). The tissue management shared resource is supported in part by the US National Cancer Institute (NCI) (1P30CA142543). J.B. is a Virginia Murchison Linthicum Scholar in Medical Research at UT Southwestern. The content herein is solely the responsibility of the authors and does not represent the official views of any of the granting agencies.

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Authors and Affiliations

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

    Samuel Peña-Llopis, Silvia Vega-Rubín-de-Celis, Andrea Pavía-Jiménez, Shanshan Wang, Toshinari Yamasaki, Leah Zhrebker, Sharanya Sivanand, Patrick Spence & James Brugarolas

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

    Samuel Peña-Llopis, Silvia Vega-Rubín-de-Celis, Andrea Pavía-Jiménez, Shanshan Wang, Toshinari Yamasaki, Leah Zhrebker, Sharanya Sivanand, Patrick Spence & James Brugarolas

  3. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Samuel Peña-Llopis, Silvia Vega-Rubín-de-Celis, Andrea Pavía-Jiménez, Shanshan Wang, Toshinari Yamasaki, Leah Zhrebker, Sharanya Sivanand, Patrick Spence, Pia Banerji Summerour, Xian-Jin Xie & James Brugarolas

  4. Illumina, Inc., San Diego, California, USA

    Arnold Liao, Nan Leng, Tina Hambuch, Suneer Jain, Marc Laurent & Christian D Haudenschild

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

    Lisa Kinch & Nick Grishin

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

    Yair Lotan, Vitaly Margulis & Arthur I Sagalowsky

  7. Department of Clinical Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Pia Banerji Summerour

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

    Wareef Kabbani & Payal Kapur

  9. Illumina Cambridge, Ltd., Little Chesterford, UK

    S W Wendy Wong, Mark T Ross & David R Bentley

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  1. Samuel Peña-Llopis
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Contributions

S.P.-L. processed, managed and extracted nucleic acids from tissues, evaluated and validated mutations, and performed bioinformatic analyses on the exome data, as well as copy-number, gene expression and statistical analyses. S.V.-R.-d.-C. was responsible for most biochemical studies using cell lines and tumorgrafts. A.L., T.H., S.J. and M.L. supervised the whole-genome sequencing process, performed quality control measures and were responsible for the primary SNV analysis in the clinical laboratory. N.L. analyzed exome sequences under the supervision of C.D.H. A.P.-J. and P.S. helped with tissue processing and histology. S.W. helped with functional studies in UMRC6 cells. T.Y. assisted in mutation validation and mouse studies. L.Z. reviewed patient's records. L.K. and N.G. performed in silico structural analyses for BAP1 and PBRM1. S.S. maintained the tumorgrafts and processed tissues. Y.L., V.M. and A.I.S. provided tissues and cell lines and assisted with the procurement of samples from the index subject. P.B.S. was the index subject's genetic counselor. W.K. and P.K. evaluated the pathology slides, and P.K. was responsible for the IHC assays. X.-J.X. performed statistical analyses and revised statistics. S.W.W.W. performed the indel analysis. M.T.R. and D.R.B. supervised and managed the genome sequencing and annotation process. J.B. conceived the study, designed experiments, analyzed the data and wrote the manuscript, with input from S.P.-L. and other authors.

Corresponding author

Correspondence to James Brugarolas.

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Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–10 and Supplementary Tables 1–10 (PDF 3634 kb)

Supplementary Data 1

Patient and tumor characteristics with mutation and IHC results (XLSX 288 kb)

Supplementary Data 2

List of unvalidated mutations found in exome sequencing with predictions based on validation analysis (XLSX 43 kb)

Supplementary Data 3

Evaluation of mutations in PBRM1, SETD2, and KDM5C in ccRCC from COSMIC database (XLSX 31 kb)

Supplementary Data 4

Heatmap of statistically significant probes distinguishing BAP1- and PBRM1-deficient tumors/tumorgrafts from wild-type tumors/tumorgrafts (XLSX 4634 kb)

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Peña-Llopis, S., Vega-Rubín-de-Celis, S., Liao, A. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44, 751–759 (2012). https://doi.org/10.1038/ng.2323

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