Abstract LB-125: Germline mutations in BAP1 predispose to melanocytic nevi and melanoma

We describe an autosomal-dominant syndrome characterized by multiple non-pigmented, exophytic melanocytic nevi and an increased susceptibility for melanoma, caused by germline mutations in the histone deubiquitinase BAP1. To identify the causative alterations, we performed comprehensive genomic analyses in two unrelated families with numerous dermal nevi composed largely of large, epithelioid melanocytes with abundant amphophilic cytoplasm and large, pleomorphic, vesicular nuclei with prominent nucleoli. Both families each had one proband with uveal melanoma, and three probands in one family had cutaneous melanoma. Array-based comparative genomic hybridization (aCGH) revealed losses of parts of or the entire chromosome 3 in 11 of 22 neoplasms studied. Genotypic analyses revealed that the deletions invariably affected the chromosome from the unaffected parent. Genome partitioning of the minimally deleted region on chromosome 3p21 followed by massively parallel sequencing revealed two different inactivating germline mutations of the BAP1 tumor suppressor gene that in both families segregated with the phenotype. In almost all tumors the remaining wild type BAP1 allele was eliminated by deletion, separate inactivating mutations, or loss of heterozygosity. 35 of 40 nevi (88%) showed mutations in BRAF, while the uveal melanomas had mutations in GNAQ. Our data identify BAP1 as a highly penetrant susceptibility gene for melanocytic neoplasia. Somatic BAP1 mutations have recently been reported in uveal melanoma and linked to the metastatic phenotype. Our observation of frequent bi-allelic inactivation of BAP1 in nevi indicates that the role of BAP1 in melanocytic neoplasia is more complex, and may differ depending on other factors such as the type of melanocyte (uveal or cutaneous) and the co-existing oncogenic mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-125. doi:10.1158/1538-7445.AM2011-LB-125