Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.
J Natl Cancer Inst
; 110(12): 1328-1341, 2018 12 01.
Article
in En
| MEDLINE
| ID: mdl-30517737
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tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS.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.
Full text:
1
Database:
MEDLINE
Main subject:
Neoplastic Syndromes, Hereditary
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Germ-Line Mutation
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Genetic Predisposition to Disease
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Tumor Suppressor Proteins
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Ubiquitin Thiolesterase
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Genetic Association Studies
Type of study:
Etiology_studies
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Prognostic_studies
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Risk_factors_studies
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Systematic_reviews
Limits:
Female
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Humans
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Male
Language:
En
Year:
2018
Type:
Article