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

Abstract

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

Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers

“…A recent report identified two families with germline BAP1 mutations that presented with UM, cutaneous melanoma, and multiple naevi18 indicating that cutaneous melanoma and naevi may be part of the cancer phenotype in patients with germline BAP1 mutations. Whether other cancers observed in our family, such as mesothelioma, testicular cancer, and adrenocortical carcinoma, are part of the cancer phenotype caused by germline BAP1 alteration remains to be investigated.…”

Loss of BAP1 Expression Is Very Rare in Pancreatic Ductal Adenocarcinoma

“…BAP1 is a tumour suppressor gene which has been implicated in an autosomal dominant hereditary tumour predisposition syndrome associated with heterozygous germline mutation [ 8 , 9 , 16 ]. Previous studies have demonstrated the robustness and reliability of BAP1 IHC in detecting double hit inactivation/mutation in multiple tumours including uveal melanoma [ 25 , 26 ], cutaneous melanoma [ 10 , 21 , 27 ], malignant mesothelioma [ 16 , 28 ], and renal cell carcinoma [ 14 ]. This was the first known study which specifically investigated BAP1 IHC in a large cohort of PDAC patients.…”

“…[ 8 ] BAP1 has recently been reported to have a tumour suppressor role by way of transcription regulation, chromatin modification, and DNA damage response [ 9 ], and the BAP1 gene has been shown to conform to Knudson’s classic two-hit model, whereby biallelic inactivation leads to tumorigenesis with or without germline mutation [ 8 ]. Biallelic inactivation and mutations of BAP1 have been associated with a number of malignancies, including cutaneous melanocytic melanomas [ 10 , 11 ], mesothelioma [ 9 , 11 – 13 ] and renal cell carcinomas [ 9 , 14 ].…”

NeuCode Proteomics Reveals Bap1 Regulation of Metabolism

“…Bap1 has received considerable attention for its mutational spectrum in cancer (Carbone et al, 2013; Schalken et al, 2010; Testa et al, 2011; Wiesner et al, 2011). Bap-interacting proteins are consistent among cell types and tissues (Dey et al, 2012; Machida et al, 2009; Misaghi et al, 2009; Scheuermann et al, 2010; Yu et al, 2010), with several showing roles in metabolic homeostasis (Bond and Hanover, 2015; Iwata et al, 2013; Izawa et al, 2015).…”

“…Brca1-associated protein (Bap1) is a deubiquitinating enzyme whose loss of function is associated with multiple human cancers (Carbone et al, 2013; Schalken et al, 2010; Testa et al, 2011; Wiesner et al, 2011). Bap1 knockout is embryonic lethal in mice and its conditional deletion triggers myeloproliferation, splenomegaly, and thrombocytopenia (Dey et al, 2012).…”