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- Title
Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.
- Authors
Walpole, Sebastian; Pritchard, Antonia L; Cebulla, Colleen M; Pilarski, Robert; Stautberg, Meredith; Davidorf, Frederick H; Fouchardière, Arnaud de la; Cabaret, Odile; Golmard, Lisa; Stoppa-Lyonnet, Dominique; Garfield, Erin; Njauw, Ching-Ni; Cheung, Mitchell; Turunen, Joni A; Repo, Pauliina; Järvinen, Reetta-Stiina; Doorn, Remco van; Jager, Martine J; Luyten, Gregorius P M; Marinkovic, Marina
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS.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.<bold>Results: </bold>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).<bold>Conclusions: </bold>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.
- Subjects
PHENOTYPES; GERM cells; MESOTHELIOMA; TUMOR suppressor genes; GENOTYPES
- Publication
JNCI: Journal of the National Cancer Institute, 2018, Vol 110, Issue 12, p1328
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djy171