Tumor Predisposition Syndrome, Uveal Melanoma and Mesothelioma via the BAP1 Gene

Germline BRCA1–associated protein 1 (BAP1) mutations have been reported to be a cause of several cancer types, including uveal melanoma (UM), and mesothelioma. UM is the most common primary intraocular tumor in adults (Goldstein et al. Nature Genetics 43(10):925-926, 2011). Mesothelioma is a rare form of cancer that develops in the mesothelium, the protective lining that covers many of the internal organs of the body. It is usually caused by exposure to asbestos. Only a small fraction of individuals exposed to asbestos have mesothelioma, suggesting that individuals with this type of cancer may have a genetic predisposition caused by BAP1 germline mutations (Testa et al. Nature Genetics 43(10):1022-5, 2011). Other less frequent cancer types which BAP1 germline mutations may have a role in include cutaneous melanoma, non-melanoma skin, ovarian, breast, renal, pancreatic, lung carcinoma and meningiomas (Goldstein et al. Nature Genetics 43(10):925-926, 2011; Abdel-Rahman et al. J Med Genet 48:856-859, 2011). Germline BAP1 mutations may also be associated with a more aggressive ocular melanoma phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (i.e. COMMON syndrome) (Njauw et al. Plos One 7(4): e35295, 2012). The complete phenotypic spectrum of tumors in BAP1 mutation carriers remains to be accurately defined. BAP1 germline mutations have been suggested to result in a single disorder with different cancer spectrums and varying degrees of penetrance (Wiesner et al. J Clin Oncol 30(32):e337-40, 2012).

BAP1 is a tumor suppressor gene that encodes a deubiquitinating enzyme containing numerous functional domains, including the ubiquitin C-terminal hydrolase (UCH) domain, a host cell factor-1 (HCF-1) binding domain and binding domains for BRCA1 and BARD1. BAP1 has been functionally implicated in numerous biologic processes, including chromatin dynamics, DNA damage response, and regulation of the cell cycle and cell growth (Goldstein et al. Nature Genetics 43(10):925-926, 2011). BAP1-related diseases are inherited in an autosomal dominant manner. Interestingly, monosomy of chromosome 3 is the most common somatic alteration in UM, reported in about 50% of primary tumors, and associated with aggressive tumors (Abdel-Rahman et al. J Med Genet 48:856-859, 2011). Approximately 50% of uveal melanomas harbor somatic BAP1 mutations (Harbour et al. Science 330:1410-13, 2010), and somatic mutations have also been found in mesotheliomas (Bott et al. Nat Genet 43:668-672, 2011). Germline BAP1 mutations include nonsense, splicing, and small insertions and deletions (Human Gene Mutation Database).

The clinical sensitivity of BAP1 germline mutations in patients with BAP1-related tumors is currently unknown.

This test provides full coverage of all coding exons of the BAP1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.