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 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
AU - Hayward, Nicholas K.
AU - Abdel Rahman, Mohamed H.
N1 - Funding Information:
This work was supported by an Australian Government Research Training Program Scholarship (SW); the National Health and Medical Research Council of Australia (NH, AP, JP, MH, HH, JS, SW, BG, SW, PJ); the Patti Blow Research Fund in Ophthalmology (MHA and FHD);
Publisher Copyright:
© 2018 Oxford University Press. All Rights Reserved.
PY - 2018/12/1
Y1 - 2018/12/1
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tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS.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.
UR - http://www.scopus.com/inward/record.url?scp=85058870474&partnerID=8YFLogxK
U2 - 10.1093/jnci/djy171
DO - 10.1093/jnci/djy171
M3 - Review article
C2 - 30517737
AN - SCOPUS:85058870474
SN - 0027-8874
VL - 110
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 12
M1 - djy171
ER -