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Review
. 2018 Dec 1;110(12):1328-1341.
doi: 10.1093/jnci/djy171.

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

Sebastian Walpole  1   2 Antonia L Pritchard  1   3 Colleen M Cebulla  4 Robert Pilarski  5 Meredith Stautberg  5 Frederick H Davidorf  4 Arnaud de la Fouchardière  6 Odile Cabaret  7 Lisa Golmard  8 Dominique Stoppa-Lyonnet  8   9   10 Erin Garfield  11 Ching-Ni Njauw  12 Mitchell Cheung  13 Joni A Turunen  14   15 Pauliina Repo  14   15 Reetta-Stiina Järvinen  14   15 Remco van Doorn  16 Martine J Jager  17 Gregorius P M Luyten  17 Marina Marinkovic  17 Cindy Chau  17 Miriam Potrony  18   19 Veronica Höiom  20 Hildur Helgadottir  20 Lorenza Pastorino  21 William Bruno  21 Virginia Andreotti  21 Bruna Dalmasso  21 Giulia Ciccarese  21 Paola Queirolo  22 Luca Mastracci  23 Karin Wadt  24 Jens Folke Kiilgaard  25 Michael R Speicher  26 Natasha van Poppelen  27   28 Emine Kilic  28 Rana'a T Al-Jamal  29 Irma Dianzani  30 Marta Betti  30 Carsten Bergmann  31   32 Sandro Santagata  33 Sonika Dahiya  34 Saleem Taibjee  35 Jo Burke  36 Nicola Poplawski  37   38 Sally J O'Shea  39 Julia Newton-Bishop  40 Julian Adlard  40 David J Adams  41 Anne-Marie Lane  42 Ivana Kim  42 Sonja Klebe  43 Hilary Racher  44 J William Harbour  45 Michael L Nickerson  46 Rajmohan Murali  47 Jane M Palmer  1 Madeleine Howlie  1 Judith Symmons  1 Hayley Hamilton  1 Sunil Warrier  48 William Glasson  48 Peter Johansson  1 Carla Daniela Robles-Espinoza  41   49 Raul Ossio  49 Annelies de Klein  28 Susana Puig  19   20 Paola Ghiorzo  11 Maartje Nielsen  50 Tero T Kivelä  15 Hensin Tsao  12   51 Joseph R Testa  13 Pedram Gerami  21   52 Marc-Henri Stern  8   9 Brigitte Bressac-de Paillerets  7   53 Mohamed H Abdel-Rahman  4   5   54 Nicholas K Hayward  1
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Free PMC article
Review

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

Sebastian Walpole et al. J Natl Cancer Inst. .
Free PMC article

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.

Figures

Figure 1.
Figure 1.
Reported missense variants plotted proportional to their frequency along the BAP1 gene with the functional domains shown. Variants that have evidence supporting pathogenicity are marked as red. The four blocks underneath each variant indicate their presence in the indicated databases. Database versions used for these metadata were: ClinVar 20170705, COSMIC v81 20170508, dbSNP 20170710, and gnomAD r2.0.1. BARD1 = BARD1 binding domain; BRCA1 = BRCA1 binding domain; cosmic = Catalogue of Somatic Mutations in Cancer; CCD = coiled-coil domain; dbSNP = Database of Single-Nucleotide Polymorphisms; gnomAD = Genome Aggregation Database; HBM = HCF binding motif (minimal tetrapeptide HCF1 binding motif); HCFC1 = HCFC1 binding domain; NLS = nuclear localization signal; UCH = ubiquitin carboxy-terminal hydrolase; ULD = Uch37-like domain; YY1 = YY1 binding domain.
Figure 2.
Figure 2.
The age of onset of all tumors presenting in variant carriers included in this study shown as box and whisker plots. Tumors are grouped together in the “all” group and then broken down into subgroups of the main BAP1-associated tumors. CM = cutaneous melanoma; Meso = mesothelioma; Renal = nonmelanoma of skin, liver, and meningioma; UM = uveal melanoma. All tumors are separated into the type of variant of the individual. M = missense; N = null. Tumors of carriers with missense variants that have evidence supporting pathogenicity (ie, those asterisked in Supplementary Table 2, available online) are marked red. P values were calculated using a two-sided Mann-Whitney test.

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