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Rigshospitalet - en del af Københavns Universitetshospital

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


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  • 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
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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.

TidsskriftJournal of the National Cancer Institute
Udgave nummer12
Sider (fra-til)1328-1341
Antal sider14
StatusUdgivet - 2018

ID: 56212476