Sebastian Walpole1,2, Antonia L Pritchard1,3, Colleen M Cebulla4, Robert Pilarski5, Meredith Stautberg5, Frederick H Davidorf4, Arnaud de la Fouchardière6, Odile Cabaret7, Lisa Golmard8, Dominique Stoppa-Lyonnet8,9,10, Erin Garfield11, Ching-Ni Njauw12, Mitchell Cheung13, Joni A Turunen14,15, Pauliina Repo14,15, Reetta-Stiina Järvinen14,15, Remco van Doorn16, Martine J Jager17, Gregorius P M Luyten17, Marina Marinkovic17, Cindy Chau17, Miriam Potrony18,19, Veronica Höiom20, Hildur Helgadottir20, Lorenza Pastorino21, William Bruno21, Virginia Andreotti21, Bruna Dalmasso21, Giulia Ciccarese21, Paola Queirolo22, Luca Mastracci23, Karin Wadt24, Jens Folke Kiilgaard25, Michael R Speicher26, Natasha van Poppelen27,28, Emine Kilic28, Rana'a T Al-Jamal29, Irma Dianzani30, Marta Betti30, Carsten Bergmann31,32, Sandro Santagata33, Sonika Dahiya34, Saleem Taibjee35, Jo Burke36, Nicola Poplawski37,38, Sally J O'Shea39, Julia Newton-Bishop40, Julian Adlard40, David J Adams41, Anne-Marie Lane42, Ivana Kim42, Sonja Klebe43, Hilary Racher44, J William Harbour45, Michael L Nickerson46, Rajmohan Murali47, Jane M Palmer1, Madeleine Howlie1, Judith Symmons1, Hayley Hamilton1, Sunil Warrier48, William Glasson48, Peter Johansson1, Carla Daniela Robles-Espinoza41,49, Raul Ossio49, Annelies de Klein28, Susana Puig19,20, Paola Ghiorzo11, Maartje Nielsen50, Tero T Kivelä15, Hensin Tsao12,51, Joseph R Testa13, Pedram Gerami21,52, Marc-Henri Stern8,9, Brigitte Bressac-de Paillerets7,53, Mohamed H Abdel-Rahman4,5,54, Nicholas K Hayward1. 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.
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.
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.
Authors: Jill A Ohar; Mitchell Cheung; Jacqueline Talarchek; Suzanne E Howard; Timothy D Howard; Mary Hesdorffer; Hongzhuang Peng; Frank J Rauscher; Joseph R Testa Journal: Cancer Res Date: 2015-12-30 Impact factor: 12.701
Authors: K A W Wadt; L G Aoude; P Johansson; A Solinas; A Pritchard; O Crainic; M T Andersen; J F Kiilgaard; S Heegaard; L Sunde; B Federspiel; J Madore; J F Thompson; S W McCarthy; A Goodwin; H Tsao; G Jönsson; K Busam; R Gupta; J M Trent; A-M Gerdes; K M Brown; R A Scolyer; N K Hayward Journal: Clin Genet Date: 2014-11-06 Impact factor: 4.438
Authors: Robert Pilarski; Colleen M Cebulla; James B Massengill; Karan Rai; Thereasa Rich; Louise Strong; Barbara McGillivray; Mary-Jill Asrat; Frederick H Davidorf; Mohamed H Abdel-Rahman Journal: Genes Chromosomes Cancer Date: 2013-11-15 Impact factor: 5.006
Authors: Melissa J Landrum; Jennifer M Lee; Mark Benson; Garth R Brown; Chen Chao; Shanmuga Chitipiralla; Baoshan Gu; Jennifer Hart; Douglas Hoffman; Wonhee Jang; Karen Karapetyan; Kenneth Katz; Chunlei Liu; Zenith Maddipatla; Adriana Malheiro; Kurt McDaniel; Michael Ovetsky; George Riley; George Zhou; J Bradley Holmes; Brandi L Kattman; Donna R Maglott Journal: Nucleic Acids Res Date: 2018-01-04 Impact factor: 16.971
Authors: Neil Farquhar; Sophie Thornton; Sarah E Coupland; Judy M Coulson; Joseph J Sacco; Yamini Krishna; Heinrich Heimann; Azzam Taktak; Colleen M Cebulla; Mohamed H Abdel-Rahman; Helen Kalirai Journal: J Pathol Clin Res Date: 2017-11-13
Authors: Reyka G Jayasinghe; Song Cao; Qingsong Gao; Michael C Wendl; Nam Sy Vo; Sheila M Reynolds; Yanyan Zhao; Héctor Climente-González; Shengjie Chai; Fang Wang; Rajees Varghese; Mo Huang; Wen-Wei Liang; Matthew A Wyczalkowski; Sohini Sengupta; Zhi Li; Samuel H Payne; David Fenyö; Jeffrey H Miner; Matthew J Walter; Benjamin Vincent; Eduardo Eyras; Ken Chen; Ilya Shmulevich; Feng Chen; Li Ding Journal: Cell Rep Date: 2018-04-03 Impact factor: 9.423
Authors: Maria I Carlo; A Ari Hakimi; Grant D Stewart; Gennady Bratslavsky; James Brugarolas; Ying-Bei Chen; W Marston Linehan; Eamonn R Maher; Maria J Merino; Kenneth Offit; Victor E Reuter; Brian Shuch; Jonathan A Coleman Journal: Eur Urol Date: 2019-07-18 Impact factor: 20.096
Authors: Getachew Boru; Timothy W Grosel; Robert Pilarski; Meredith Stautberg; James B Massengill; Joanne Jeter; Arun Singh; Meghan J Marino; Joseph P McElroy; Frederick H Davidorf; Colleen M Cebulla; Mohamed H Abdel-Rahman Journal: Genes Chromosomes Cancer Date: 2019-04-23 Impact factor: 5.006
Authors: Raffit Hassan; Betsy Morrow; Anish Thomas; Tom Walsh; Ming K Lee; Suleyman Gulsuner; Meghana Gadiraju; Vasiliki Panou; Shaojian Gao; Idrees Mian; Javed Khan; Mark Raffeld; Snehal Patel; Liqiang Xi; Jun S Wei; Mary Hesdorffer; Jingli Zhang; Kathleen Calzone; Arpita Desai; Emerson Padiernos; Christine Alewine; David S Schrump; Seth M Steinberg; Hedy L Kindler; Mary-Claire King; Jane E Churpek Journal: Proc Natl Acad Sci U S A Date: 2019-04-11 Impact factor: 11.205
Authors: Michele Carbone; Prasad S Adusumilli; H Richard Alexander; Paul Baas; Fabrizio Bardelli; Angela Bononi; Raphael Bueno; Emanuela Felley-Bosco; Francoise Galateau-Salle; David Jablons; Aaron S Mansfield; Michael Minaai; Marc de Perrot; Patricia Pesavento; Valerie Rusch; David T Severson; Emanuela Taioli; Anne Tsao; Gavitt Woodard; Haining Yang; Marjorie G Zauderer; Harvey I Pass Journal: CA Cancer J Clin Date: 2019-07-08 Impact factor: 508.702
Authors: Marjorie G Zauderer; Gowtham Jayakumaran; Mariel DuBoff; Liying Zhang; Jasmine H Francis; David H Abramson; Andrea Cercek; Garrett M Nash; Alexander Shoushtari; Paul Chapman; Sandra D'Angelo; Angela G Arnold; Beth Siegel; Megan Harlan Fleischut; Andy Ni; Andreas Rimner; Valerie W Rusch; Prasad S Adusumilli; William Travis; Jennifer L Sauter; Ahmet Zehir; Diana Mandelker; Marc Ladanyi; Mark Robson Journal: J Thorac Oncol Date: 2019-07-16 Impact factor: 15.609
Authors: Michele Carbone; Sarah T Arron; Bruce Beutler; Angela Bononi; Webster Cavenee; James E Cleaver; Carlo M Croce; Alan D'Andrea; William D Foulkes; Giovanni Gaudino; Joanna L Groden; Elizabeth P Henske; Ian D Hickson; Paul M Hwang; Richard D Kolodner; Tak W Mak; David Malkin; Raymond J Monnat; Flavia Novelli; Harvey I Pass; John H Petrini; Laura S Schmidt; Haining Yang Journal: Nat Rev Cancer Date: 2020-05-29 Impact factor: 60.716
Authors: Mohamed H Abdel-Rahman; Klarke M Sample; Robert Pilarski; Tomas Walsh; Timothy Grosel; Daniel Kinnamon; Getachew Boru; James B Massengill; Lynn Schoenfield; Ben Kelly; David Gordon; Peter Johansson; Meghan J DeBenedictis; Arun Singh; Silvia Casadei; Frederick H Davidorf; Peter White; Andrew W Stacey; James Scarth; Ellie Fewings; Marc Tischkowitz; Mary-Claire King; Nicholas K Hayward; Colleen M Cebulla Journal: Ophthalmology Date: 2019-11-18 Impact factor: 12.079