Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide Journal Article
| Authors: | 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.; Chau, C.; Potrony, M.; Höiom, V.; Helgadottir, H.; Pastorino, L.; Bruno, W.; Andreotti, V.; Dalmasso, B.; Ciccarese, G.; Queirolo, P.; Mastracci, L.; Wadt, K.; Kiilgaard, J. F.; Speicher, M. R.; van Poppelen, N.; Kilic, E.; Al-Jamal, R. T.; Dianzani, I.; Betti, M.; Bergmann, C.; Santagata, S.; Dahiya, S.; Taibjee, S.; Burke, J.; Poplawski, N.; O'Shea, S. J.; Newton-Bishop, J.; Adlard, J.; Adams, D. J.; Lane, A. M.; Kim, I.; Klebe, S.; Racher, H.; Harbour, J. W.; Nickerson, M. L.; Murali, R.; Palmer, J. M.; Howlie, M.; Symmons, J.; Hamilton, H.; Warrier, S.; Glasson, W.; Johansson, P.; Robles-Espinoza, C. D.; Ossio, R.; de Klein, A.; Puig, S.; Ghiorzo, P.; Nielsen, M.; Kivelä, T. T.; Tsao, H.; Testa, J. R.; Gerami, P.; Stern, M. H.; Paillerets, B. B.; Abdel-Rahman, M. H.; Hayward, N. K. |
| Article Title: | Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide |
| 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tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS.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. |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 110 |
| Issue: | 12 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 2018-12-01 |
| Start Page: | 1328 |
| End Page: | 1341 |
| Language: | English |
| DOI: | 10.1093/jnci/djy171 |
| PROVIDER: | scopus |
| PMCID: | PMC6292796 |
| PUBMED: | 30517737 |
| DOI/URL: | |
| Notes: | J. Natl. Cancer Inst. -- Export Date: 2 January 2019 -- Article -- Source: Scopus C2 - 30517737 |
