BAP1-Tumor Predisposition Syndrome (BAP1-TPDS)
BAP1-TPDS is a hereditary cancer syndrome caused by germline mutations in the BAP1 gene. It predisposes patients to a variety of cancers and benign lesions. The four main cancers – uveal melanoma (UM)[1, 2], malignant mesothelioma (MMe)[3], renal cell carcinoma (RCC) [4] and cutaneous melanoma (CM)[5] – are the core tumors of the syndrome. However, other cancers could be part of the clinical phenotype[1, 3-6].
It is not uncommon that affected individuals develop more than one type of primary cancer during their lifetime. In general, the median age of onset of these tumors is earlier than in the general population. Because of the limited number of families reported to date – the penetrance, natural history, and frequencies of the BAP1-associated tumors are yet to be determined.
The frequency of BAP1 mutation carriers in the general population is unknown but it is most likely extremely low (one estimate puts it at 1/53015 individuals[7]. The carrier frequency in cancer patients is reported to be 0.077%, with higher frequency in patients with UM (1%)[8], MMe (1%)[8], and RCC (0.78%)[8]
We published a seminal consortium paper in 2018 in the Journal of the National Cancer Institute where we examined the clinical phenotype of the largest international cohort of BAP1-germline variant carrying families (374 variant carriers and 635 ungenotyped relatives in 181 families – 75 previously unpublished). We found that in null variant carriers the penetrance of tumors was 85%; confirming UM (25%), MMe (20%), CM (17%) and RCC (10%) as the core of BAP1-TPDS. Furthermore, we extended the spectrum to include cholangiocarcinoma, meningioma and basal cell carcinoma. We also detailed how carriers with some missense variants can exhibit the BAP1-TPDS phenotype.
OMIM: http://omim.org/entry/614327
Genereviews: https://www.ncbi.nlm.nih.gov/books/NBK390611/
NIH Genetics Home Reference: https://ghr.nlm.nih.gov/condition/bap1-tumor-predisposition-syndrome#
1. Abdel-Rahman, M.H., et al., Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet, 2011. 48(12): p. 856-9.
2.Harbour, J.W., et al., Frequent mutation of BAP1 in metastasizing uveal melanomas. Science, 2010. 330(6009): p. 1410-3.
3.Testa, J.R., et al., Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet, 2011. 43(10): p. 1022-5.
4.Popova, T., et al., Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet, 2013. 92(6): p. 974-80.
5. Wiesner, T., et al., Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet, 2011. 43(10): p. 1018-21.
6.Walpole, S., et al., Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide. J Natl Cancer Inst, 2018.
7. Massengill, J.B., et al., Analysis of the exome aggregation consortium (ExAC) database suggests that the BAP1-tumor predisposition syndrome is underreported in cancer patients. Genes Chromosomes Cancer, 2018. 57(9): p. 478-481.
8. Huang, K.L., et al., Pathogenic Germline Variants in 10,389 Adult Cancers. Cell, 2018. 173(2): p. 355-370 e14.