Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide

Sebastian Walpole; Antonia L. Pritchard; Colleen M. Cebulla; Robert Pilarski; Meredith Stautberg; Frederick H. Davidorf; Arnaud De La Fouchardière; Odile Cabaret; Lisa Golmard; Dominique Stoppa-Lyonnet; Erin Garfield; Ching Ni Njauw; Mitchell Cheung; Joni A. Turunen; Pauliina Repo; Reetta Stiina Järvinen; Remco Van Doorn; Martine J. Jager; Gregorius P.M. Luyten; Marina Marinkovic; Cindy Chau; Miriam Potrony; Veronica Höiom; Hildur Helgadottir; Lorenza Pastorino; William Bruno; Virginia Andreotti; Bruna Dalmasso; Giulia Ciccarese; Paola Queirolo; Luca Mastracci; Karin Wadt; Jens Folke Kiilgaard; Michael R. Speicher; Natasha Van Poppelen; Emine Kilic; Rana T. Al-Jamal; Irma Dianzani; Marta Betti; Carsten Bergmann; Sandro Santagata; Sonika Dahiya; Saleem Taibjee; Jo Burke; Nicola Poplawski; Sally J. O'Shea; Julia Newton-Bishop; Julian Adlard; David J. Adams; Anne Marie Lane; Nicholas K. Hayward; Mohamed H. Abdel Rahman

doi:10.1093/jnci/djy171

Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide

Sebastian Walpole, Antonia L. Pritchard, Colleen M. Cebulla, Robert Pilarski, Meredith Stautberg, Frederick H. Davidorf, Arnaud De La Fouchardière, Odile Cabaret, Lisa Golmard, Dominique Stoppa-Lyonnet, Erin Garfield, Ching Ni Njauw, Mitchell Cheung, Joni A. Turunen, Pauliina Repo, Reetta Stiina Järvinen, Remco Van Doorn, Martine J. Jager, Gregorius P.M. Luyten, Marina MarinkovicCindy Chau, Miriam Potrony, Veronica Höiom, Hildur Helgadottir, Lorenza Pastorino, William Bruno, Virginia Andreotti, Bruna Dalmasso, Giulia Ciccarese, Paola Queirolo, Luca Mastracci, Karin Wadt, Jens Folke Kiilgaard, Michael R. Speicher, Natasha Van Poppelen, Emine Kilic, Rana T. Al-Jamal, Irma Dianzani, Marta Betti, Carsten Bergmann, Sandro Santagata, Sonika Dahiya, Saleem Taibjee, Jo Burke, Nicola Poplawski, Sally J. O'Shea, Julia Newton-Bishop, Julian Adlard, David J. Adams, Anne Marie Lane, Nicholas K. Hayward, Mohamed H. Abdel Rahman

Research output: Contribution to journal › Review article › peer-review

168 Scopus citations

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.

Original language	English
Article number	djy171
Journal	Journal of the National Cancer Institute
Volume	110
Issue number	12
DOIs	https://doi.org/10.1093/jnci/djy171
State	Published - Dec 1 2018

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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., ... Abdel Rahman, M. H. (2018). Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide. Journal of the National Cancer Institute, 110(12), Article djy171. https://doi.org/10.1093/jnci/djy171

@article{71792686f27644529c8e23388c2e5ada,

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.",

author = "Sebastian Walpole and Pritchard, {Antonia L.} and Cebulla, {Colleen M.} and Robert Pilarski and Meredith Stautberg and Davidorf, {Frederick H.} and {De La Fouchardi{\`e}re}, Arnaud and Odile Cabaret and Lisa Golmard and Dominique Stoppa-Lyonnet and Erin Garfield and Njauw, {Ching Ni} and Mitchell Cheung and Turunen, {Joni A.} and Pauliina Repo and J{\"a}rvinen, {Reetta Stiina} and {Van Doorn}, Remco and Jager, {Martine J.} and Luyten, {Gregorius P.M.} and Marina Marinkovic and Cindy Chau and Miriam Potrony and Veronica H{\"o}iom and Hildur Helgadottir and Lorenza Pastorino and William Bruno and Virginia Andreotti and Bruna Dalmasso and Giulia Ciccarese and Paola Queirolo and Luca Mastracci and Karin Wadt and Kiilgaard, {Jens Folke} and Speicher, {Michael R.} and {Van Poppelen}, Natasha and Emine Kilic and Al-Jamal, {Rana T.} and Irma Dianzani and Marta Betti and Carsten Bergmann and Sandro Santagata and Sonika Dahiya and Saleem Taibjee and Jo Burke and Nicola Poplawski and O'Shea, {Sally J.} and Julia Newton-Bishop and Julian Adlard and Adams, {David J.} and Lane, {Anne Marie} and Hayward, {Nicholas K.} and {Abdel Rahman}, {Mohamed H.}",

year = "2018",

month = dec,

day = "1",

doi = "10.1093/jnci/djy171",

language = "English",

volume = "110",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

number = "12",

}

Walpole, S, Pritchard, AL, Cebulla, CM, Pilarski, R, Stautberg, M, Davidorf, FH, De La Fouchardière, A, Cabaret, O, Golmard, L, Stoppa-Lyonnet, D, Garfield, E, Njauw, CN, Cheung, M, Turunen, JA, Repo, P, Järvinen, RS, Van Doorn, R, Jager, MJ, Luyten, GPM, 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, 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, Hayward, NK & Abdel Rahman, MH 2018, 'Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide', Journal of the National Cancer Institute, vol. 110, no. 12, djy171. https://doi.org/10.1093/jnci/djy171

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.

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 -

Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide

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