Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families

• Published in: PloS one Vol. 7; no. 4; p. e35295
• Main Authors: Njauw, Ching-Ni Jenny, Kim, Ivana, Piris, Adriano, Gabree, Michele, Taylor, Michael, Lane, Anne Marie, DeAngelis, Margaret M, Gragoudas, Evangelos, Duncan, Lyn M, Tsao, Hensin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.04.2012; Public Library of Science (PLoS)
• Subjects: Adult; Biology; BRCA1 protein; Breast cancer; C-Terminus; Cancer; Cell cycle; Cell growth; Cohort Studies; Deactivation; Eye - metabolism; Eye - pathology; Eye Neoplasms - genetics; Eye Neoplasms - pathology; Family; Family medical history; Female; Gene mutation; Genetic Predisposition to Disease; Genetics; Germ-Line Mutation; Hospitals; Humans; Inactivation; Male; Medicine; Melanoma; Melanoma - genetics; Melanoma - pathology; Mesothelioma; Metastases; Metastasis; Middle Aged; Mutation; Neoplasm Metastasis - genetics; Neoplasms; Pathology; Patients; Pedigree; Retina; Risk assessment; Skin - metabolism; Skin - pathology; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Trends; Tumor Suppressor Proteins - genetics; Ubiquitin Thiolesterase - genetics; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035295

BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome. To characterize BAP1's contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds. Germline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition. Germline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive BAP1 inactivation.