TY - JOUR
T1 - Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide
AU - Walpole, Sebastian
AU - Pritchard, Antonia L
AU - Cebulla, Colleen M
AU - Pilarski, Robert
AU - Stautberg, Meredith
AU - Davidorf, Frederick H
AU - de la Fouchardière, Arnaud
AU - Cabaret, Odile
AU - Golmard, Lisa
AU - Stoppa-Lyonnet, Dominique
AU - Garfield, Erin
AU - Njauw, Ching-Ni
AU - Cheung, Mitchell
AU - Turunen, Joni A
AU - Repo, Pauliina
AU - Järvinen, Reetta-Stiina
AU - van Doorn, Remco
AU - Jager, Martine J
AU - Luyten, Gregorius P M
AU - Marinkovic, Marina
AU - Chau, Cindy
AU - Potrony, Miriam
AU - Höiom, Veronica
AU - Helgadottir, Hildur
AU - Pastorino, Lorenza
AU - Bruno, William
AU - Andreotti, Virginia
AU - Dalmasso, Bruna
AU - Ciccarese, Giulia
AU - Queirolo, Paola
AU - Mastracci, Luca
AU - Wadt, Karin
AU - Kiilgaard, Jens Folke
AU - Speicher, Michael R
AU - van Poppelen, Natasha
AU - Kilic, Emine
AU - Al-Jamal, Rana'a T
AU - Dianzani, Irma
AU - Betti, Marta
AU - Bergmann, Carsten
AU - Santagata, Sandro
AU - Dahiya, Sonika
AU - Taibjee, Saleem
AU - Burke, Jo
AU - Poplawski, Nicola
AU - O'Shea, Sally J
AU - Newton-Bishop, Julia
AU - Adlard, Julian
AU - Adams, David J
AU - Lane, Anne-Marie
N1 - © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
PY - 2018/12/4
Y1 - 2018/12/4
N2 - 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tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS.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.
AB - 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.
U2 - 10.1093/jnci/djy171
DO - 10.1093/jnci/djy171
M3 - Article
C2 - 30517737
SN - 0027-8874
VL - 110
SP - 1328
EP - 1341
JO - JNCI: Journal of the National Cancer Institute
JF - JNCI: Journal of the National Cancer Institute
IS - 12
ER -
