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https://hdl.handle.net/2440/117882
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Type: | Journal article |
Title: | Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide |
Author: | Walpole, S. Pritchard, A.L. Cebulla, C.M. Pilarski, R. Stautberg, M. Davidorf, F.H. de la Fouchardière, A. Cabaret, O. Golmard, L. Stoppa-Lyonnet, D. Garfield, E. Njauw, C.N. Cheung, M. Turunen, J.A. Repo, P. Järvinen, R.S. van Doorn, R. Jager, M.J. Luyten, G.P.M. Marinkovic, M. et al. |
Citation: | Journal of the National Cancer Institute, 2018; 110(12):1328-1341 |
Publisher: | Oxford University Press |
Issue Date: | 2018 |
ISSN: | 0027-8874 1460-2105 |
Statement of Responsibility: | Sebastian Walpole Antonia L Pritchard Colleen M Cebulla Robert Pilarski Meredith Stautberg ... Nicola Poplawski ... et al. |
Abstract: | Background:The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. Methods:We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. Results:The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001). Conclusions:This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research. |
Keywords: | Phenotype; mesothelioma; neoplasms; pathogenicity; bap1 gene |
Rights: | © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) |
DOI: | 10.1093/jnci/djy171 |
Published version: | http://dx.doi.org/10.1093/jnci/djy171 |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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