Abstract

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma1, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.

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Acknowledgements

We are grateful to the affected individuals and their families for their participation in this study. We thank M. Bianchi, C. Menges, I. Pagano, J.D. Rowley and D.C. Ward for advice and review of the manuscript. We also thank J. Talarchek and R. Harrington for technical assistance, K. Aquino-Michaels for assisting in the collection of samples and clinical information, S.C. Jhanwar for providing some of the mesothelioma cell lines, A. Vachani for blood and tissue samples from one member of the L family and B. Luo for providing exome sequence data. This work was supported by US National Institutes of Health (NIH) grants P01CA-114047, P30CA-06927 and P30CA-71789, by the AACR-Landon Award for International Collaboration in Cancer Research to M. Carbone, N.J.C., H.I.P., J.R.T., M.T. and H.Y., and by the Local No. 14 Mesothelioma Fund of the International Association of Heat and Frost Insulators & Allied Workers to J.R.T.

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Affiliations

  1. Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    • Joseph R Testa
    • , Mitchell Cheung
    • , Jianming Pei
    • , Yinfei Tan
    •  & Eleonora Sementino
  2. Department of Medicine, University of Chicago, Chicago, Illinois, USA.

    • Jennifer E Below
    •  & Nancy J Cox
  3. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.

    • Nancy J Cox
  4. Earth Sciences Department, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia.

    • A Umran Dogan
  5. Department of Chemical and Biochemical Engineering, University of Iowa, Iowa City, Iowa, USA.

    • A Umran Dogan
  6. New York University, Langone Medical Center and Cancer Center, New York, New York, USA.

    • Harvey I Pass
    •  & Sandra Trusa
  7. Mesothelioma Applied Research Foundation, Alexandria, Virginia, USA.

    • Mary Hesdorffer
  8. University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii, USA.

    • Masaki Nasu
    • , Amy Powers
    • , Zeyana Rivera
    • , Sabahattin Comertpay
    • , Mika Tanji
    • , Giovanni Gaudino
    • , Haining Yang
    •  & Michele Carbone
  9. Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, Hawaii, USA.

    • Masaki Nasu
    • , Zeyana Rivera
    • , Sabahattin Comertpay
    •  & Mika Tanji
  10. Department of Pathology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA.

    • Haining Yang

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Contributions

J.R.T. led the team at Fox Chase Cancer Center (FCCC; M. Cheung, J.P., Y.T. and E.S.) that first identified and characterized the BAP1 mutations and genomic alterations in the two families with high incidence of mesothelioma, performed the splicing and functional assays, and discovered BAP1 mutations in sporadic tumors and cell lines. N.J.C. designed and directed the genetic linkage analysis studies performed by J.E.B. H.I.P. treated many of these patients and together with S.T. and M.H. provided the tumor samples, DNA and clinical information. A.U.D. performed the mineralogical studies. M. Carbone conceived the project, assembled the families and the entire research group, diagnosed mesotheliomas and led the team at University of Hawaii Cancer Center (UHCC; M.N., A.P., Z.R., S.C., M.T., G.G. and H.Y.) that confirmed the mutations in the two families and discovered germline and somatic mutations in sporadic mesotheliomas. M.N. led the experimental work conducted by the UHCC team. J.R.T. and M. Carbone wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Joseph R Testa or Michele Carbone.

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DOI

https://doi.org/10.1038/ng.912

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