Abstract
Common acquired melanocytic nevi are benign neoplasms that are composed of small, uniform melanocytes and are typically present as flat or slightly elevated pigmented lesions on the skin. We describe two families with a new autosomal dominant syndrome characterized by multiple, skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected individuals developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of BAP1, which encodes a ubiquitin carboxy-terminal hydrolase. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histological similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.
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Acknowledgements
We are indebted to all participating subjects for their enthusiastic participation in the study. We thank W. Stieber for clinical photography, U. Schmidbauer for providing histotechnical services, M. Leversha for performing FISH, A. Heguy for supporting sequencing, M. Asher for immunohistochemistry, H. Al-Ahmadie for assistance with the histological images and P. Dillinger for helping to collect the tissue samples. T.W. was supported by a Max-Kade Fellowship and expresses special thanks to H. Kerl for supporting, encouraging and inspiring his academic interests. A.C.O. is supported by the Austrian Science Fund (J3013) and K.G.G. by the Deutsche Forschungsgemeinschaft (GR 3671/1-1a). This work was funded by grants from the US National Institutes of Health (R01 CA131524), Geoffrey Beene Cancer Research Center (CC 66270), the American Skin Association (all to B.C.B.), the Andrew Sabin Family Foundation (to K.O.), the European Commission (GENINCA, contract no. HEALTH-F2-2008-202230) and the Jubilaeumsfonds of the Oesterreichische Nationalbank (13837).
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Project planning and experimental design: T.W., B.C.B. and M.R.S. Review of clinical phenotypes: T.W., I.F., I.W. and J.C.B. Review of histology and immunohistology: T.W., B.C.B., H.K., R.M., L.C., I.F., A.R. and A.O. FISH analysis: T.W. and G.P. Sample collection: T.W., H.K., W.W., K.O. and D.A. aCGH: T.W. and A.C.O. Linkage analysis: A.C.O. and C.W. Mutation analysis: T.W., P.U. and S.L. Next-generation sequencing and data analysis: T.W., A.V., A.E.L., N.D.S. and M.P. Manuscript writing: T.W., B.C.B., R.M., M.R.S. and K.G.G. Revision of the manuscript: all authors.
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Wiesner, T., Obenauf, A., Murali, R. et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet 43, 1018–1021 (2011). https://doi.org/10.1038/ng.910
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DOI: https://doi.org/10.1038/ng.910
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