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.

  • Article
  • Published:

BAP1 loss defines a new class of renal cell carcinoma

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Referenced accessions

Protein Data Bank

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

References

  1. Siegel, R., Ward, E., Brawley, O. & Jemal, A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J. Clin. 61, 212–236 (2011).

    Article  Google Scholar 

  2. Baldewijns, M.M. et al. Genetics and epigenetics of renal cell cancer. Biochim. Biophys. Acta 1785, 133–155 (2008).

    CAS  PubMed  Google Scholar 

  3. Brugarolas, J. Renal-cell carcinoma—molecular pathways and therapies. N. Engl. J. Med. 356, 185–187 (2007).

    Article  CAS  Google Scholar 

  4. Latif, F. et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260, 1317–1320 (1993).

    Article  CAS  Google Scholar 

  5. Gnarra, J.R. et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat. Genet. 7, 85–90 (1994).

    Article  CAS  Google Scholar 

  6. Nickerson, M.L. et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin. Cancer Res. 14, 4726–4734 (2008).

    Article  CAS  Google Scholar 

  7. Beroukhim, R. et al. Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res. 69, 4674–4681 (2009).

    Article  CAS  Google Scholar 

  8. Chen, M. et al. Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays. Int. J. Cancer 125, 2342–2348 (2009).

    Article  CAS  Google Scholar 

  9. Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).

    Article  CAS  Google Scholar 

  10. Dalgliesh, G.L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).

    Article  CAS  Google Scholar 

  11. van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521–523 (2009).

    Article  CAS  Google Scholar 

  12. Fuhrman, S.A., Lasky, L.C. & Limas, C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am. J. Surg. Pathol. 6, 655–663 (1982).

    Article  CAS  Google Scholar 

  13. Bretheau, D. et al. Prognostic value of nuclear grade of renal cell carcinoma. Cancer 76, 2543–2549 (1995).

    Article  CAS  Google Scholar 

  14. Ficarra, V. et al. Prognostic and therapeutic impact of the histopathologic definition of parenchymal epithelial renal tumors. Eur. Urol. 58, 655–668 (2010).

    Article  Google Scholar 

  15. Pantuck, A.J. et al. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer 109, 2257–2267 (2007).

    Article  CAS  Google Scholar 

  16. Sabatini, D.M. mTOR and cancer: insights into a complex relationship. Nat. Rev. Cancer 6, 729–734 (2006).

    Article  CAS  Google Scholar 

  17. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    Article  CAS  Google Scholar 

  18. Kucejova, B. et al. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol. Cancer Res. 9, 1255–1265 (2011).

    Article  CAS  Google Scholar 

  19. Brugarolas, J. Research translation and personalized medicine. in Renal Cell Carcinoma (eds. Figlin, R.A., Rathmell, W.K. & Rini, B.I.) 161–191 (Springer New York, 2012).

  20. Hahn, S.A. et al. Allelotype of pancreatic adenocarcinoma using xenograft enrichment. Cancer Res. 55, 4670–4675 (1995).

    CAS  PubMed  Google Scholar 

  21. Sivanand, S. et al. A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma. Sci. Transl. Med. 4, 137ra75 (2012).

    Article  Google Scholar 

  22. Lee, S.T. et al. Mutations of the P gene in oculocutaneous albinism, ocular albinism, and Prader-Willi syndrome plus albinism. N. Engl. J. Med. 330, 529–534 (1994).

    Article  CAS  Google Scholar 

  23. Suzuki, T. et al. Six novel P gene mutations and oculocutaneous albinism type 2 frequency in Japanese albino patients. J. Invest. Dermatol. 120, 781–783 (2003).

    Article  CAS  Google Scholar 

  24. Gasparre, G., Romeo, G., Rugolo, M. & Porcelli, A.M. Learning from oncocytic tumors: why choose inefficient mitochondria? Biochim. Biophys. Acta 1807, 633–642 (2011).

    Article  CAS  Google Scholar 

  25. Jensen, D.E. et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16, 1097–1112 (1998).

    Article  CAS  Google Scholar 

  26. Ventii, K.H. et al. BRCA1-associated protein–1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res. 68, 6953–6962 (2008).

    Article  CAS  Google Scholar 

  27. Eletr, Z.M. & Wilkinson, K.D. An emerging model for BAP1's role in regulating cell cycle progression. Cell Biochem. Biophys. 60, 3–11 (2011).

    Article  CAS  Google Scholar 

  28. Harbour, J.W. et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330, 1410–1413 (2010).

    Article  CAS  Google Scholar 

  29. Wiesner, T. et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat. Genet. 43, 1018–1021 (2011).

    Article  CAS  Google Scholar 

  30. Bott, M. et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat. Genet. 43, 668–672 (2011).

    Article  CAS  Google Scholar 

  31. Misaghi, S. et al. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol. Cell. Biol. 29, 2181–2192 (2009).

    Article  CAS  Google Scholar 

  32. Nishikawa, H. et al. BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity. Cancer Res. 69, 111–119 (2009).

    Article  CAS  Google Scholar 

  33. Machida, Y.J., Machida, Y., Vashisht, A.A., Wohlschlegel, J.A. & Dutta, A. The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. J. Biol. Chem. 284, 34179–34188 (2009).

    Article  CAS  Google Scholar 

  34. Scheuermann, J.C. et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465, 243–247 (2010).

    Article  CAS  Google Scholar 

  35. Yu, H. et al. The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression. Mol. Cell. Biol. 30, 5071–5085 (2010).

    Article  CAS  Google Scholar 

  36. Kristie, T.M., Liang, Y. & Vogel, J.L. Control of α-herpesvirus IE gene expression by HCF-1 coupled chromatin modification activities. Biochim. Biophys. Acta 1799, 257–265 (2010).

    Article  CAS  Google Scholar 

  37. Knez, J., Piluso, D., Bilan, P. & Capone, J.P. Host cell factor–1 and E2F4 interact via multiple determinants in each protein. Mol. Cell. Biochem. 288, 79–90 (2006).

    Article  CAS  Google Scholar 

  38. Tyagi, S., Chabes, A.L., Wysocka, J. & Herr, W. E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases. Mol. Cell 27, 107–119 (2007).

    Article  CAS  Google Scholar 

  39. Wysocka, J., Myers, M.P., Laherty, C.D., Eisenman, R.N. & Herr, W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3–K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev. 17, 896–911 (2003).

    Article  CAS  Google Scholar 

  40. Yokoyama, A. et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol. Cell. Biol. 24, 5639–5649 (2004).

    Article  CAS  Google Scholar 

  41. Narayanan, A., Ruyechan, W.T. & Kristie, T.M. The coactivator host cell factor–1 mediates Set1 and MLL1 H3K4 trimethylation at herpesvirus immediate early promoters for initiation of infection. Proc. Natl. Acad. Sci. USA 104, 10835–10840 (2007).

    Article  CAS  Google Scholar 

  42. Liang, Y., Vogel, J.L., Narayanan, A., Peng, H. & Kristie, T.M. Inhibition of the histone demethylase LSD1 blocks α-herpesvirus lytic replication and reactivation from latency. Nat. Med. 15, 1312–1317 (2009).

    Article  CAS  Google Scholar 

  43. Smith, E.R. et al. A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16. Mol. Cell. Biol. 25, 9175–9188 (2005).

    Article  CAS  Google Scholar 

  44. Stokes, M.P. et al. Profiling of UV-induced ATM/ATR signaling pathways. Proc. Natl. Acad. Sci. USA 104, 19855–19860 (2007).

    Article  CAS  Google Scholar 

  45. Matsuoka, S. et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160–1166 (2007).

    Article  CAS  Google Scholar 

  46. Kaelin, W. Jr. Molecular biology of clear cell renal carcinoma. in Renal Cell Carcinoma (eds. Figlin, R.A., Rathmell, W.K. & Rini, B.I.) 27–47 (Springer New York, 2012).

  47. Xu, X. et al. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 148, 886–895 (2012).

    Article  CAS  Google Scholar 

  48. Chapman-Fredricks, J.R. et al. Adult renal cell carcinoma with rhabdoid morphology represents a neoplastic dedifferentiation analogous to sarcomatoid carcinoma. Ann. Diagn. Pathol. 15, 333–337 (2011).

    Article  Google Scholar 

  49. Gökden, N. et al. Renal cell carcinoma with rhabdoid features. Am. J. Surg. Pathol. 24, 1329–1338 (2000).

    Article  Google Scholar 

  50. Abdel-Rahman, M.H. et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J. Med. Genet. 48, 856–859 (2011).

    Article  CAS  Google Scholar 

  51. Testa, J.R. et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat. Genet. 43, 1022–1025 (2011).

    Article  CAS  Google Scholar 

  52. Wysocka, J., Reilly, P.T. & Herr, W. Loss of HCF-1-chromatin association precedes temperature-induced growth arrest of tsBN67 cells. Mol. Cell. Biol. 21, 3820–3829 (2001).

    Article  CAS  Google Scholar 

  53. Guo, G. et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat. Genet. 44, 17–19 (2012).

    Article  CAS  Google Scholar 

  54. Bentley, D.R. et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008).

    Article  CAS  Google Scholar 

  55. Olshen, A.B., Venkatraman, E.S., Lucito, R. & Wigler, M. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557–572 (2004).

    Article  Google Scholar 

  56. Peña-Llopis, S. et al. Regulation of TFEB and V-ATPases by mTORC1. EMBO J. 30, 3242–3258 (2011).

    Article  Google Scholar 

  57. Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate—a practical and powerful approach to multiple testing. J. R. Stat. Soc., B 57, 289–300 (1995).

    Google Scholar 

  58. Steiger, J.H. Tests for comparing elements of a correlation matrix. Psychol. Bull. 87, 245–251 (1980).

    Article  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Samuel Peña-Llopis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Vega-Rubín-de-Celis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arnold Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nan Leng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrea Pavía-Jiménez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shanshan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshinari Yamasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leah Zhrebker
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sharanya Sivanand
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Patrick Spence
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lisa Kinch
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tina Hambuch
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Suneer Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yair Lotan
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Vitaly Margulis
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Arthur I Sagalowsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Pia Banerji Summerour
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Wareef Kabbani
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. S W Wendy Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Nick Grishin
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Marc Laurent
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Xian-Jin Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Christian D Haudenschild
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Mark T Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. David R Bentley
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Payal Kapur
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. James Brugarolas
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2323

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer