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

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Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide

Journal article

Open access

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, …

JNCI : Journal of the National Cancer Institute, Vol.110(12), pp.1328-1341

2018-12-01

DOI: https://doi.org/10.1093/jnci/djy171

PMCID: PMC6292796

PMID: 30517737

Abstract

Genetic Predisposition to Disease

Genetic Association Studies

Risk Assessment

Gene Frequency

Humans

Neoplastic Syndromes, Hereditary - diagnosis

Genotype

Male

Ubiquitin Thiolesterase - genetics

Neoplastic Syndromes, Hereditary - epidemiology

Phenotype

Tumor Suppressor Proteins - genetics

Age of Onset

Alleles

Germ-Line Mutation

Female

Neoplastic Syndromes, Hereditary - genetics

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. 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. 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). 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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.297 Asbestos & Mesothelioma; 1.297.780 Asbestos
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

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Title: Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide
Creators: Sebastian Walpole - University of Queensland, Brisbane, QLD, Australia
Antonia L Pritchard - The University of the Highlands and Islands, Inverness, UK
Colleen M Cebulla - Department of Ophthalmology and Visual Science, The Ohio State University, Columbus, OH
Robert Pilarski - Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH
Meredith Stautberg - Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH
Frederick H Davidorf - Department of Ophthalmology and Visual Science, The Ohio State University, Columbus, OH
Arnaud de la Fouchardière - Département of Biopathology, Centre Leon Bérard, Lyon, France
Odile Cabaret - Département de Biopathologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Lisa Golmard - Département De Biologie Des Tumeurs, Institut Curie, Paris, France
Dominique Stoppa-Lyonnet - Sorbonne Paris Cité, University Paris-Descartes, Paris, France
Erin Garfield - Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL
Ching-Ni Njauw - Department of Dermatology, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA
Mitchell Cheung - Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA
Joni A Turunen - Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Pauliina Repo - Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Reetta-Stiina Järvinen - Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Remco van Doorn - Department of Dermatology, LUMC, Leiden, The Netherlands
Martine J Jager - Department of Ophthalmology, LUMC, Leiden, The Netherlands
Gregorius P M Luyten - Department of Ophthalmology, LUMC, Leiden, The Netherlands
Marina Marinkovic - Department of Ophthalmology, LUMC, Leiden, The Netherlands
Cindy Chau - Department of Ophthalmology, LUMC, Leiden, The Netherlands
Miriam Potrony - Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain
Veronica Höiom - Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Hildur Helgadottir - Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Lorenza Pastorino - Department of Internal Medicine and Medical Specialties and Genetics of Rare Cancers, University of Genoa, Ospedale Policlinico San Martino, Genoa, Italy
William Bruno - Department of Internal Medicine and Medical Specialties and Genetics of Rare Cancers, University of Genoa, Ospedale Policlinico San Martino, Genoa, Italy
Virginia Andreotti - Department of Internal Medicine and Medical Specialties and Genetics of Rare Cancers, University of Genoa, Ospedale Policlinico San Martino, Genoa, Italy
Bruna Dalmasso - Department of Internal Medicine and Medical Specialties and Genetics of Rare Cancers, University of Genoa, Ospedale Policlinico San Martino, Genoa, Italy
Giulia Ciccarese - Department of Internal Medicine and Medical Specialties and Genetics of Rare Cancers, University of Genoa, Ospedale Policlinico San Martino, Genoa, Italy
Paola Queirolo - Medical Oncology Unit, Ospedale Policlinico San Martino, Genoa, Italy
Luca Mastracci - Department of Surgical and Diagnostic Sciences, Pathology Unit, University of Genoa and Ospedale Policlinico San Martino, Genoa, Italy
Karin Wadt - Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark
Jens Folke Kiilgaard - Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Michael R Speicher - Institute of Human Genetics, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz, Austria
Natasha van Poppelen - Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
Emine Kilic - Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
Rana'a T Al-Jamal - Department of Ophthalmology, Ocular Oncology Service, Helsinki University Central Hospital, Helsinki, Finland
Irma Dianzani - Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
Marta Betti - Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
Carsten Bergmann - Department of Medicine IV, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany
Sandro Santagata - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Sonika Dahiya - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
Saleem Taibjee - Department of Dermatology, Dorset County Hospital NHS Foundation Trust, Dorchester, UK
Jo Burke - Tasmanian Clinical Genetics Service, Royal Hobart Hospital, TAS, Australia
Nicola Poplawski - University Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia
Sally J O'Shea - Dermatology Department, Mater Private Hospital Cork, Citygate, Mahon, Cork, Ireland
Julia Newton-Bishop - Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
Julian Adlard - Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
David J Adams - Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK
Anne-Marie Lane - Department of Ophthalmology, Ocular Melanoma Center and Retina Service, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA
Ivana Kim - Department of Ophthalmology, Ocular Melanoma Center and Retina Service, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA
Sonja Klebe - Department of Anatomical Pathology, Flinders University and SA Pathology at Flinders Medical Centre, Adelaide, SA, Australia
Hilary Racher - Impact Genetics, Bowmanville, Ontario, Canada
J William Harbour - Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL
Michael L Nickerson - Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD
Rajmohan Murali - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
Jane M Palmer - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Madeleine Howlie - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Judith Symmons - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Hayley Hamilton - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Sunil Warrier - Queensland Ocular Oncology Service, The Terrace Eye Centre, Brisbane, QLD, Australia
William Glasson - Queensland Ocular Oncology Service, The Terrace Eye Centre, Brisbane, QLD, Australia
Peter Johansson - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Carla Daniela Robles-Espinoza - Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Santiago de Querétaro, Mexico
Raul Ossio - Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Santiago de Querétaro, Mexico
Annelies de Klein - Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
Susana Puig - Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Paola Ghiorzo - Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL
Maartje Nielsen - Department of Clinical Genetics, LUMC, Leiden, The Netherlands
Tero T Kivelä - Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Hensin Tsao - Massachusetts General Hospital Cancer Center, Boston, MA
Joseph R Testa - Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA
Pedram Gerami - The Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL
Marc-Henri Stern - Institut Curie, PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France
Brigitte Bressac-de Paillerets - INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, PSL, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
Mohamed H Abdel-Rahman - Department of Pathology, Menoufiya University, Shebin El-Kom, Egypt
Nicholas K Hayward - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Publication Details: JNCI : Journal of the National Cancer Institute, Vol.110(12), pp.1328-1341
Grant note: R21 CA191943 / NCI NIH HHS P30 CA016058 / NCI NIH HHS K24 CA149202 / NCI NIH HHS 12-0023 / Worldwide Cancer Research 204562/Z/16/Z / Wellcome Trust 10589 / Cancer Research UK R01 CA175691 / NCI NIH HHS UL1 RR025755 / NCRR NIH HHS K08 EY022672 / NEI NIH HHS P30 CA008748 / NCI NIH HHS
Academic Unit: Miller School of Medicine; UMMG Department of Neurology; UMMG Department of Ophthalmology
Language: English
Resource Type: Journal article
PMID: 30517737
PMCID: PMC6292796
Record Identifier: 991031597609002976