期刊
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
卷 110, 期 12, 页码 1328-1341出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djy171
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资金
- Australian Government Research Training Program Scholarship
- National Health and Medical Research Council of Australia
- Patti Blow Research Fund in Ophthalmology
- National Eye Institute of the National Institutes of Health [K08EY022672]
- National Cancer Institute [R21CA191943]
- Ohio Lions Eye Research Foundation
- Dutch Cancer Society [UL2012-5489, 2014-6905]
- Italian Ministry of Health 5 x 1000 per la Ricerca Corrente to Ospedale Policlinico San Martino
- Helsinki University Hospital Research Funds [TYH2017218]
- Sigrid Juselius Foundation
- Finnish Cancer Foundation
- Eye and Tissue Bank Foundation
- Folkhalsan Research Foundation
- Evald and Hilda Nissi Foundation
- Paulo Foundation
- Mary and Georg C. Ehrnrooth Foundation
- National Institutes of Health [K24CA149202]
- Spanish Fondo de Investigaciones Sanitarias [PI15/00716, PI15/00956]
- CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain
- European Development Regional Fund A way to achieve Europe ERDF
- Catalan Government, Spain [AGAUR 2014SGR603, 2017SGR1134]
- European Commission [LSHC-CT-2006018702]
- European Commission
- National Cancer Institute (NCI) of the National Institutes of Health (NIH) [CA83115]
- Fundacio La Marato de TV3, Catalonia, Spain [201331-30]
- Fundacion Cientifica de la Asociacion Espanola Contra el Cancer, Spain [GCB15152978SOEN]
- CERCA Programme/Generalitat de Catalunya
- Instituto de Salud Carlos III, Spain [FI14/00231]
- National Institutes of Health, National Cancer Institute [CA175691]
- Collaborative Ophthalmic Research Rotterdam (1.1.1)
- Wealtheon
- Bontius Stichting
- LSBS
- Stiching Blinden Penning
- ANVVB
- Oogfonds
- Karolinska Institutet's foundation grants for eye research
- NIH/NCI Cancer Center Support Grant [P30 CA008748]
- COACYT PhD fellowship
- Wellcome Trust [204562/Z/16/Z]
- UNAM PAPIIT [200318]
- Wellcome Trust [204562/Z/16/Z] Funding Source: Wellcome Trust
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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