Letter | Published:

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

Nature Genetics volume 43, pages 668672 (2011) | Download Citation

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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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.

Author information

Affiliations

  1. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Matthew Bott
    • , Marie Brevet
    • , Shigeki Shimizu
    • , Tatsuo Ito
    • , Lu Wang
    • , Maureen F Zakowski
    •  & Marc Ladanyi
  2. Department of Surgery, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA.

    • Matthew Bott
    •  & Valerie Rusch
  3. Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Barry S Taylor
    • , Boris Reva
    •  & Chris Sander
  4. National Centre for Asbestos Disease Research, School of Medicine and Pharmacology, University of Western Australia, Sir Charles Gairdner Hospital, Nedlands, Australia.

    • Jenette Creaney
    •  & Richard A Lake
  5. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Robert Delsite
    •  & Simon Powell
  6. Epidemiology-Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Qin Zhou
    • , Ronglai Shen
    •  & Adam Olshen
  7. Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Marc Ladanyi

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Marc Ladanyi.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1–11 and Supplementary Figures 1–9

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    Supplementary Data 1

    Basic clinical and pathologic data on the set of 53 subjects with MPMs

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DOI

https://doi.org/10.1038/ng.855

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