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BAP1 is one of a handful of genes known to be mutated in ocular melanoma (OM), somatically (de novo in the tumor) or inherited through the germline. To characterize the contribution of BAP1 alterations to the risk for metastatic OM and cutaneous melanoma (CM), investigators sequenced BAP1 in 100 patients with OM (50 metastatic, 50 nonmetastatic) and 200 patients with CM listed in their melanoma registry or seen at a pigmented lesion center.
Heterozygous germline mutations were found in 4 of 50 patients with metastatic OM and in none with nonmetastatic OM (P=0.059). To test whether BAP1 inactivation was linked to familial CM-OM, the researchers sequenced BAP1 in 200 patients with an increased hereditary risk for CM. They found mutations in 2 of 7 CM patients from CM-OM families and 1 of 193 patients from non-OM families (P=0.003).
Notably, patients with BAP1 mutations had characteristic, orange-red, oval-shaped plaques or dome-shaped papules that were nevoid melanoma or highly atypical NEvoid Melanoma-like Melanocytic Proliferations (NEMMPs). Analysis of seven lesions from one CM-OM kindred revealed loss of heterozygosity for BAP1, with concomitant BRAFV600E mutation in four lesions but no GNAQ mutations.
Njauw C-NJ et al. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS ONE 2012 Apr; 7:e35295. (http://dx.doi.org/10.1371/journal.pone.0035295)
Comment
This important study shows that BAP1 mutations are associated with a higher risk for metastatic ocular melanoma, which is linked to cutaneous melanoma in CM-OM families and to characteristic nevoid lesions, significantly extending a prior report (Nat Genet 2011; 43:1018) of germline BAP1 mutations in melanoma. Because other visceral malignancies (lung cancer, mesothelioma; Nat Genet 2011; 43:1022) are also found in these kindreds, the authors propose the term COMMON syndrome (Cutaneous/Ocular Melanomas, atypical Melanocytic proliferations and Other internal Neoplasms). BAP1 function in this context remains to be elucidated, and affected pathways may be distinct from others strongly implicated in melanoma, such as NRAS/BRAF and CDKN2A/CDK4. BAP1 mutations are rare, but genotyping might identify high-risk patients who would benefit from more intense surveillance and targeted therapies should they become available.