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’a 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; Ivana Kim; Sonja Klebe; Hilary Racher; J. William Harbour; Michael L. Nickerson; Rajmohan Murali; Jane M. Palmer; Madeleine Howlie; Judith Symmons; Hayley Hamilton; Sunil Warrier; William Glasson; Peter Johansson; Carla Daniela Robles-Espinoza; Raul Ossio; Annelies de Klein; Susana Puig; Paola Ghiorzo; Maartje Nielsen; Tero T. Kivelä; Hensin Tsao; Joseph R. Testa; Pedram Gerami; Marc Henri Stern; Brigitte Bressac-de-Paillerets; Mohamed H. Abdel-Rahman; Nicholas K. Hayward

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 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’a 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, Ivana Kim, Sonja Klebe, Hilary Racher, J. William Harbour, Michael L. Nickerson, Rajmohan Murali, Jane M. Palmer, Madeleine Howlie, Judith Symmons, Hayley Hamilton, Sunil Warrier, William Glasson, Peter Johansson, Carla Daniela Robles-Espinoza, Raul Ossio, Annelies de Klein, Susana Puig, Paola Ghiorzo, Maartje Nielsen, Tero T. Kivelä, Hensin Tsao, Joseph R. Testa, Pedram Gerami, Marc Henri Stern, Brigitte Bressac-de-Paillerets, Mohamed H. Abdel-Rahman, Nicholas K. Hayward

Cancer Prevention and Control (CPC)

Queensland Institute of Medical Research
University of Queensland
University of the Highlands and Islands
Ohio State University
Georgetown University
Centre Léon Bérard
Université Paris-Sud
Institut Curie
Université Paris Cité
Northwestern University
Massachusetts General Hospital
Fox Chase Cancer Center
Folkhalsan
University of Helsinki
Leiden University
Center for Biomedical Network Research on Rare Diseases (CIBERER)
University of Barcelona
Karolinska Institutet
IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro
University of Copenhagen
Medical University of Graz
Erasmus University Rotterdam
Helsinki University Hospital
University of Eastern Piedmont
Bioscientia Institut für Medizinische Diagnostik GmbH
University of Freiburg
Harvard University
Brigham and Women's Hospital
Washington University St. Louis
Dorset County Hospital NHS Foundation Trust
Royal Hobart Hospital
University of Melbourne
Peter Maccallum Cancer Centre
Royal Adelaide Hospital
University of Adelaide
Mater Private Hospital
Leeds Teaching Hospitals NHS Trust
University of Cambridge
Yorkshire Regional Genetics Service
Centre for Cancer Genetic Epidemiology
Cheshire and Merseyside Clinical Genetics Service
Wellcome Sanger Institute
Flinders University
Impact Genetics
University of Miami
National Institutes of Health
Memorial Sloan-Kettering Cancer Center
Berghofer Medical Research Institute
The Terrace Eye Centre
Universidad Nacional Autónoma de México
Massachusetts General Hospital Cancer Center
INSERM U830
Université Paris-Saclay
Menoufia University

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

242 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
Pages (from-to)	1328-1341
Number of pages	14
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

Keywords

Age of Onset
Alleles
Female
Gene Frequency
Genetic Association Studies
Genetic Predisposition to Disease
Genotype
Germ-Line Mutation
Humans
Male
Neoplastic Syndromes, Hereditary/diagnosis
Phenotype
Risk Assessment
Tumor Suppressor Proteins/genetics
Ubiquitin Thiolesterase/genetics

Access to Document

10.1093/jnci/djy171

Cite this

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., ... Hayward, N. K. (2018). Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide. Journal of the National Cancer Institute, 110(12), 1328-1341. Article djy171. https://doi.org/10.1093/jnci/djy171

@article{a5e87a5e12a84150826a1cca34dfeb35,

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.",

keywords = "Age of Onset, Alleles, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, Male, Neoplastic Syndromes, Hereditary/diagnosis, Phenotype, Risk Assessment, Tumor Suppressor Proteins/genetics, Ubiquitin Thiolesterase/genetics",

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{\textquoteright}a 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{\textquoteright}Shea, \{Sally J.\} and Julia Newton-Bishop and Julian Adlard and Adams, \{David J.\} and Lane, \{Anne Marie\} and Ivana Kim and Sonja Klebe and Hilary Racher and Harbour, \{J. William\} and Nickerson, \{Michael L.\} and Rajmohan Murali and Palmer, \{Jane M.\} and Madeleine Howlie and Judith Symmons and Hayley Hamilton and Sunil Warrier and William Glasson and Peter Johansson and Robles-Espinoza, \{Carla Daniela\} and Raul Ossio and \{de Klein\}, Annelies and Susana Puig and Paola Ghiorzo and Maartje Nielsen and Kivel{\"a}, \{Tero T.\} and Hensin Tsao and Testa, \{Joseph R.\} and Pedram Gerami and Stern, \{Marc Henri\} and Brigitte Bressac-de-Paillerets and Abdel-Rahman, \{Mohamed H.\} and Hayward, \{Nicholas K.\}",

year = "2018",

month = dec,

day = "1",

doi = "10.1093/jnci/djy171",

language = "English",

volume = "110",

pages = "1328--1341",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

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, 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, Kivelä, TT, Tsao, H, Testa, JR, Gerami, P, Stern, MH, Bressac-de-Paillerets, B, Abdel-Rahman, MH & Hayward, NK 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, pp. 1328-1341. 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’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

AU - Kim, Ivana

AU - Klebe, Sonja

AU - Racher, Hilary

AU - Harbour, J. William

AU - Nickerson, Michael L.

AU - Murali, Rajmohan

AU - Palmer, Jane M.

AU - Howlie, Madeleine

AU - Symmons, Judith

AU - Hamilton, Hayley

AU - Warrier, Sunil

AU - Glasson, William

AU - Johansson, Peter

AU - Robles-Espinoza, Carla Daniela

AU - Ossio, Raul

AU - de Klein, Annelies

AU - Puig, Susana

AU - Ghiorzo, Paola

AU - Nielsen, Maartje

AU - Kivelä, Tero T.

AU - Tsao, Hensin

AU - Testa, Joseph R.

AU - Gerami, Pedram

AU - Stern, Marc Henri

AU - Bressac-de-Paillerets, Brigitte

AU - Abdel-Rahman, Mohamed H.

AU - Hayward, Nicholas K.

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.

KW - Age of Onset

KW - Alleles

KW - Female

KW - Gene Frequency

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Germ-Line Mutation

KW - Humans

KW - Male

KW - Neoplastic Syndromes, Hereditary/diagnosis

KW - Phenotype

KW - Risk Assessment

KW - Tumor Suppressor Proteins/genetics

KW - Ubiquitin Thiolesterase/genetics

UR - https://www.scopus.com/pages/publications/85058870474

U2 - 10.1093/jnci/djy171

DO - 10.1093/jnci/djy171

M3 - Review article

C2 - 30517737

SN - 0027-8874

VL - 110

SP - 1328

EP - 1341

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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Keywords

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