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The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma

Abstract

Malignant pleural mesotheliomas (MPMs) often show CDKN2A and NF2 inactivation, but other highly recurrent mutations have not been described. To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPMs. The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes. These findings implicate transcriptional deregulation in the pathogenesis of MPM.

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Figure 1: RAE analysis of genomic gains and losses in 53 MPM tumors.
Figure 2: Heat map of chromosome 3p in MPM tumors.
Figure 3: Distribution of BAP1 mutations relative to functional domains.
Figure 4: Integrated gene map showing BAP1 losses and mutations in relation to other identified genomic events in all 53 samples.
Figure 5: Relationship between the BAP1 knockdown expression signature in MPM and three published Polycomb target gene sets.

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References

  1. Illei, P.B., Rusch, V.W., Zakowski, M.F. & Ladanyi, M. Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Clin. Cancer Res. 9, 2108–2113 (2003).

    CAS  PubMed  Google Scholar 

  2. Thurneysen, C. et al. Functional inactivation of NF2/merlin in human mesothelioma. Lung Cancer 64, 140–147 (2009).

    Article  Google Scholar 

  3. Lu, Y.Y., Jhanwar, S.C., Cheng, J.Q. & Testa, J.R. Deletion mapping of the short arm of chromosome 3 in human malignant mesothelioma. Genes Chromosom. Cancer 9, 76–80 (1994).

    Article  CAS  Google Scholar 

  4. López-Ríos, F. et al. Global gene expression profiling of pleural mesotheliomas: overexpression of aurora kinases and p16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer Res. 66, 2970–2979 (2006).

    Article  Google Scholar 

  5. 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 

  6. Oestergaard, V.H. et al. Deubiquitination of FANCD2 is required for DNA crosslink repair. Mol. Cell 28, 798–809 (2007).

    Article  CAS  Google Scholar 

  7. Kim, J.M. et al. Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev. Cell 16, 314–320 (2009).

    Article  CAS  Google Scholar 

  8. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    Article  CAS  Google Scholar 

  9. Kittler, R. et al. Genome-scale RNAi profiling of cell division in human tissue culture cells. Nat. Cell Biol. 9, 1401–1412 (2007).

    Article  CAS  Google Scholar 

  10. Schlabach, M.R. et al. Cancer proliferation gene discovery through functional genomics. Science 319, 620–624 (2008).

    Article  CAS  Google Scholar 

  11. 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 

  12. 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 

  13. 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 

  14. 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 

  15. Chou, W.C. et al. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex combs-like 1 (ASXL1) mutations. Blood 116, 4086–4094 (2010).

    Article  CAS  Google Scholar 

  16. Bracken, A.P., Dietrich, N., Pasini, D., Hansen, K.H. & Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123–1136 (2006).

    Article  CAS  Google Scholar 

  17. Hassan, K.A., Chen, G., Kalemkerian, G.P., Wicha, M.S. & Beer, D.G. An embryonic stem cell-like signature identifies poorly differentiated lung adenocarcinoma but not squamous cell carcinoma. Clin. Cancer Res. 15, 6386–6390 (2009).

    Article  CAS  Google Scholar 

  18. Douglas, D. et al. BMI-1 promotes Ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res. 68, 6507–6515 (2008).

    Article  CAS  Google Scholar 

  19. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Mallery, D.L., Vandenberg, C.J. & Hiom, K. Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. EMBO J. 21, 6755–6762 (2002).

    Article  CAS  Google Scholar 

  22. 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 

  23. Fisher, C.L. et al. Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood 115, 38–46 (2010).

    Article  CAS  Google Scholar 

  24. Sowa, M.E., Bennett, E.J., Gygi, S.P. & Harper, J.W. Defining the human deubiquitinating enzyme interaction landscape. Cell 138, 389–403 (2009).

    Article  CAS  Google Scholar 

  25. Krug, L.M. et al. Potential role of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid. Clin. Lung Cancer 7, 257–261 (2006).

    Article  Google Scholar 

  26. Crisanti, M.C. et al. The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer. Mol. Cancer Ther. 8, 2221–2231 (2009).

    Article  CAS  Google Scholar 

  27. Irizarry, R.A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003).

    Article  Google Scholar 

  28. Aguirre, A.J. et al. High-resolution characterization of the pancreatic adenocarcinoma genome. Proc. Natl. Acad. Sci. USA 101, 9067–9072 (2004).

    Article  CAS  Google Scholar 

  29. Venkatraman, E.S. & Olshen, A.B. A faster circular binary segmentation algorithm for the analysis of array CGH data. Bioinformatics 23, 657–663 (2007).

    Article  CAS  Google Scholar 

  30. Smyth, G.K. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, Article3 (2004).

    Article  Google Scholar 

  31. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  32. Taylor, B.S. et al. Functional copy-number alterations in cancer. PLoS ONE 3, e3179 (2008).

    Article  Google Scholar 

  33. Brunet, J.P., Tamayo, P., Golub, T.R. & Mesirov, J.P. Metagenes and molecular pattern discovery using matrix factorization. Proc. Natl. Acad. Sci. USA 101, 4164–4169 (2004).

    Article  CAS  Google Scholar 

  34. Carrasco, D.R. et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 9, 313–325 (2006).

    Article  CAS  Google Scholar 

  35. Reva, B., Antipin, Y. & Sander, C. Determinants of protein function revealed by combinatorial entropy optimization. Genome Biol. 8, R232 (2007).

    Article  Google Scholar 

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Acknowledgements

We thank A. Holloway for help in combining MPM cell line microarray datasets, R. Levine and O. Abdel-Wahab for helpful discussions and Merck for providing PARP inhibitor MK4827. We thank A. Heguy and the personnel of the Beene Translational Oncology Core Facility (MSKCC), A. Lash and Y. Liang of the Bioinfomatics Core Facility (MSKCC), A. Viale and the personnel of the Genomics Core Facility (MSKCC) and M. Asher in the Pathology Core Facility (MSKCC). The project was supported by a generous donation from an anonymous private donor. M. Brevet was supported in part by La Fondation de France. B.S.T. is the David H. Koch Fellow in Cancer Genomics (MSKCC). R.A.L. is supported by the National Health and Medical Research Council (NHMRC) of Australia.

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Authors

Contributions

M.L. designed and oversaw the study. V.R. and M.F.Z. oversaw the tumor sample procurement and histopathologic review, respectively. S.S. performed tumor sample selection and analyte processing for tumor samples and cell lines. J.C. and R.A.L. contributed microarray data and analytes from additional cell lines. M. Bott and M.L. reviewed microarray data and selected genes for sequencing. M. Bott obtained and analyzed additional sequencing and genotyping data. M. Bott and T.I. performed functional validation experiments. M. Brevet analyzed immunohistochemistry data. L.W. performed and analyzed FISH studies. R.D. performed functional assays for DNA repair foci, and R.D. and S.P. interpreted the results. B.S.T., B.R., C.S., Q.Z., R.S. and A.O. performed statistical and bioinformatics analyses. M. Bott and M.L. drafted the manuscript. All authors contributed to critical review of the paper.

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Correspondence to Marc Ladanyi.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–11 and Supplementary Figures 1–9 (PDF 1413 kb)

Supplementary Data 1

Basic clinical and pathologic data on the set of 53 subjects with MPMs (XLSX 14 kb)

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Bott, M., Brevet, M., Taylor, B. 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). https://doi.org/10.1038/ng.855

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