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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

<div class="section"> <a class="named-anchor" id="s1">  </a> <h5 class="section-title" id="d449017e1064">Background</h5> <p id="d449017e1066">The BRCA1-associated protein-1 ( <i>BAP1</i>) tumor predisposition syndrome ( <i>BAP1</i>-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in <i>BAP1</i> 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 <i>BAP1</i>-TPDS is crucial for appropriate clinical management of <i>BAP1</i> germline variant carriers and their families, including genetic counseling and surveillance for new tumors. </p> </div><div class="section"> <a class="named-anchor" id="s2">  </a> <h5 class="section-title" id="d449017e1084">Methods</h5> <p id="d449017e1086">We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished <i>BAP1</i> germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the <i>BAP1</i>-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. </p> </div><div class="section"> <a class="named-anchor" id="s3">  </a> <h5 class="section-title" id="d449017e1095">Results</h5> <p id="d449017e1097">The 181 families carried 140 unique <i>BAP1</i> germline variants. The collated data confirmed the core tumor spectrum associated with the <i>BAP1</i>-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore <i>BAP1</i>-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 ( <i>P</i> < .001), mesothelioma ( <i>P</i> < .001), cutaneous melanoma ( <i>P</i> < .001), and nonmelanoma skin cancer ( <i>P</i> < .001). </p> </div><div class="section"> <a class="named-anchor" id="s4">  </a> <h5 class="section-title" id="d449017e1122">Conclusions</h5> <p id="d449017e1124">This analysis substantially increases the number of pathogenic <i>BAP1</i> 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 <i>BAP1</i>-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research. </p> </div>

Related collections

Author and article information

Journal

Title: JNCI: Journal of the National Cancer Institute

Publisher: Oxford University Press (OUP)

ISSN (Print): 0027-8874

ISSN (Electronic): 1460-2105

Publication date Created: December 2018

Publication date Created: December 01 2018

Publication date Created: December 04 2018

Publication date Other: December 2018

Publication date (Print): December 01 2018

Publication date (Electronic): December 04 2018

Volume: 110

Issue: 12

Pages: 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

Article

DOI: 10.1093/jnci/djy171

PMC ID: 6292796

PubMed ID: 30517737

SO-VID: fdc2f9fe-c7ea-444f-9065-bfda97be720e

License:

https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

History

Data availability:

Comments

Comment on this article

scite_

196

220

Smart Citations

196

220

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.