Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide
Journal of the National Cancer Institute , Volume 110 - Issue 12 p. 1328- 1341
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tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS.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.
|Journal of the National Cancer Institute|
|Organisation||Department of Clinical Genetics|
Walpole, S. (Sebastian), Pritchard, A.L. (Antonia L.), Cebulla, C.M. (Colleen M.), Pilarski, R, Stautberg, M. (Meredith), Davidorf, F.H. (Frederick H.), … Hayward, N.K. (Nicholas K.). (2018). Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide. Journal of the National Cancer Institute, 110(12), 1328–1341. doi:10.1093/jnci/djy171