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

      review-article
      1 , 2 , 1 , 3 , 4 , 5 , 5 , 4 , 6 , 7 , 8 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 14 , 15 , 14 , 15 , 16 , 17 , 17 , 17 , 17 , 18 , 19 , 20 , 20 , 21 , 21 , 21 , 21 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 28 , 29 , 30 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 40 , 41 , 42 , 42 , 43 , 44 , 45 , 46 , 47 , 1 , 1 , 1 , 1 , 48 , 48 , 1 , 41 , 49 , 49 , 28 , 19 , 20 , 11 , 50 , 15 , 12 , 51 , 13 , 21 , 52 , 8 , 9 , 7 , 53 , 4 , 5 , 54 , 1
      JNCI Journal of the National Cancer Institute
      Oxford University Press

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          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tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS.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.

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          Author and article information

          Journal
          J Natl Cancer Inst
          J. Natl. Cancer Inst
          jnci
          JNCI Journal of the National Cancer Institute
          Oxford University Press
          0027-8874
          1460-2105
          December 2018
          04 December 2018
          04 December 2019
          : 110
          : 12
          : 1328-1341
          Affiliations
          [1 ]QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
          [2 ]University of Queensland, Brisbane, QLD, Australia
          [3 ]The University of the Highlands and Islands, Inverness, UK
          [4 ]Department of Ophthalmology and Visual Science, The Ohio State University, Columbus, OH
          [5 ]Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH
          [6 ]Département of Biopathology, Centre Leon Bérard, Lyon, France
          [7 ]Département de Biopathologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France
          [8 ]Département De Biologie Des Tumeurs, Institut Curie, Paris, France
          [9 ]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
          [10 ]Sorbonne Paris Cité, University Paris-Descartes, Paris, France
          [11 ]Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL
          [12 ]Department of Dermatology, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA
          [13 ]Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA
          [14 ]Folkhälsan Institute of Genetics, Helsinki, Finland
          [15 ]Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
          [16 ]Department of Dermatology, LUMC, Leiden, The Netherlands
          [17 ]Department of Ophthalmology, LUMC, Leiden, The Netherlands
          [18 ]Dermatology Department, Melanoma Unit, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
          [19 ]Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain
          [20 ]Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
          [21 ]Department of Internal Medicine and Medical Specialties and Genetics of Rare Cancers, University of Genoa, Ospedale Policlinico San Martino, Genoa, Italy
          [22 ]Medical Oncology Unit, Ospedale Policlinico San Martino, Genoa, Italy
          [23 ]Department of Surgical and Diagnostic Sciences, Pathology Unit, University of Genoa and Ospedale Policlinico San Martino, Genoa, Italy
          [24 ]Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark
          [25 ]Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
          [26 ]Institute of Human Genetics, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz, Austria
          [27 ]Department of Ophthalmology
          [28 ]Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
          [29 ]Department of Ophthalmology, Ocular Oncology Service, Helsinki University Central Hospital, Helsinki, Finland
          [30 ]Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
          [31 ]Bioscientia Center for Human Genetics, Ingelheim, Germany
          [32 ]Department of Medicine IV, Faculty of Medicine, Medical Center—University of Freiburg, University of Freiburg, Freiburg, Germany
          [33 ]Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
          [34 ]Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
          [35 ]Department of Dermatology, Dorset County Hospital NHS Foundation Trust, Dorchester, UK
          [36 ]Tasmanian Clinical Genetics Service, Royal Hobart Hospital, TAS, Australia
          [37 ]Adult Genetics Unit, Medicine Directorate, Royal Adelaide Hospital, Adelaide, SA, Australia
          [38 ]University Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia
          [39 ]Dermatology Department, Mater Private Hospital Cork, Citygate, Mahon, Cork, Ireland
          [40 ]Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
          [41 ]Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK
          [42 ]Department of Ophthalmology, Ocular Melanoma Center and Retina Service, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA
          [43 ]Department of Anatomical Pathology, Flinders University and SA Pathology at Flinders Medical Centre, Adelaide, SA, Australia
          [44 ]Impact Genetics, Bowmanville, Ontario, Canada
          [45 ]Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL
          [46 ]Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD
          [47 ]Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
          [48 ]Queensland Ocular Oncology Service, The Terrace Eye Centre, Brisbane, QLD, Australia
          [49 ]Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Santiago de Querétaro, Mexico
          [50 ]Department of Clinical Genetics, LUMC, Leiden, The Netherlands
          [51 ]Massachusetts General Hospital Cancer Center, Boston, MA
          [52 ]The Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL
          [53 ]INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, PSL, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
          [54 ]Department of Pathology, Menoufiya University, Shebin El-Kom, Egypt
          Author notes

          These authors co-led this study.

          Correspondence to: Nicholas K. Hayward, PhD, Oncogenomics Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane 4006, Australia (e-mail: Nick.Hayward@ 123456qimrberghofer.edu.au ); or Mohamed H. Abdel Rahman, MD, PhD, Department of Ophthalmology, The Ohio State University Comprehensive Cancer Center, 400 W 12th Ave, Room 202 Wiseman Hall, Columbus, OH 43210 (e-mail: Mohamed.Abdel-Rahman@ 123456osumc.edu ).
          Article
          PMC6292796 PMC6292796 6292796 djy171
          10.1093/jnci/djy171
          6292796
          30517737
          fdc2f9fe-c7ea-444f-9065-bfda97be720e
          © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

          This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model ( https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

          History
          : 19 April 2018
          : 17 July 2018
          : 31 August 2018
          Page count
          Pages: 14
          Funding
          Funded by: Australian Government Research Training Program Scholarship
          Funded by: National Health and Medical Research Council of Australia
          Funded by: National Eye Institute of the National Institutes of Health
          Award ID: K08EY022672
          Award ID: R21CA191943
          Funded by: National Institutes of Health 10.13039/100000002
          Award ID: K24CA149202
          Funded by: Spanish Fondo de Investigaciones Sanitarias
          Award ID: PI15/00716
          Award ID: PI15/00956
          Funded by: National Cancer Institute 10.13039/100000054
          Funded by: National Institutes of Health 10.13039/100000002
          Award ID: CA83115
          Funded by: NIH/NCI Cancer Center
          Award ID: P30 CA008748
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