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Walpole S , Pritchard AL , Cebulla CM , Pilarski R , Stautberg M , Davidorf FH , de la Fouchardiere A , Cabaret O , Golmard L , Stoppa-Lyonnet D , Garfield E , Njauw CN , Cheung M , Turunen JA , Repo P , Jarvinen RS , van Doorn R , Jager MJ , Luyten GPM , Marinkovic M , Chau C , Potrony M , Hoiom V , Helgadottir H , Pastorino L , Bruno W , Andreotti V , Dalmasso B , Ciccarese G , Queirolo P , Mastracci L , Wadt K , Kiilgaard JF , Speicher MR , van Poppelen N , Kilic E , Al-Jamal RT , Dianzani I , Betti M , Bergmann C , Santagata S , Dahiya S , Taibjee S , Burke J , Poplawski N , O'Shea SJ , Newton-Bishop J , Adlard J , Adams DJ , Lane AM , Kim I , Klebe S , Racher H , Harbour JW , Nickerson ML , Murali R , Palmer JM , Howlie M , Symmons J , Hamilton H , Warrier S , Glasson W , Johansson P , Robles-Espinoza CD , Ossio R , de Klein A , Puig S , Ghiorzo P , Nielsen M , Kivela TT , Tsao H , Testa JR , Gerami P , Stern MH , Paillerets BB , Abdel-Rahman MH , Hayward NK
Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide
J Natl Cancer Inst. 2018 Dec 1;110(12) :1328-1341
PMID: 30517737    PMCID: PMC6292796   
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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tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS.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.
Notes
1460-2105 Walpole, Sebastian Pritchard, Antonia L Cebulla, Colleen M Pilarski, Robert Stautberg, Meredith Davidorf, Frederick H de la Fouchardiere, Arnaud Cabaret, Odile Golmard, Lisa Stoppa-Lyonnet, Dominique Garfield, Erin Njauw, Ching-Ni Cheung, Mitchell Turunen, Joni A Repo, Pauliina Jarvinen, Reetta-Stiina van Doorn, Remco Jager, Martine J Luyten, Gregorius P M Marinkovic, Marina Chau, Cindy Potrony, Miriam Hoiom, Veronica Helgadottir, Hildur Pastorino, Lorenza Bruno, William Andreotti, Virginia Dalmasso, Bruna Ciccarese, Giulia Queirolo, Paola Mastracci, Luca Wadt, Karin Kiilgaard, Jens Folke Speicher, Michael R van Poppelen, Natasha Kilic, Emine Al-Jamal, Rana'a T Dianzani, Irma Betti, Marta Bergmann, Carsten Santagata, Sandro Dahiya, Sonika Taibjee, Saleem Burke, Jo Poplawski, Nicola O'Shea, Sally J Newton-Bishop, Julia Adlard, Julian Adams, David J Lane, Anne-Marie Kim, Ivana Klebe, Sonja Racher, Hilary Harbour, J William Nickerson, Michael L Murali, Rajmohan Palmer, Jane M Howlie, Madeleine Symmons, Judith Hamilton, Hayley Warrier, Sunil Glasson, William Johansson, Peter Robles-Espinoza, Carla Daniela Ossio, Raul de Klein, Annelies Puig, Susana Ghiorzo, Paola Nielsen, Maartje Kivela, Tero T Tsao, Hensin Testa, Joseph R Gerami, Pedram Stern, Marc-Henri Paillerets, Brigitte Bressac-de Abdel-Rahman, Mohamed H Hayward, Nicholas K Journal Article United States J Natl Cancer Inst. 2018 Dec 1;110(12):1328-1341. doi: 10.1093/jnci/djy171.