Abstract
Background 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.DesignTo 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.ResultsGermline 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.ConclusionGermline 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.
Highlights
For ocular melanoma (OM), monosomy 3 is one of the most powerful independent predictors of metastasis and negative outcome [1]
Five families with deleterious germline BAP1 mutations were described including several kindreds with both ocular and cutaneous melanoma (CM) [3,4,5]. These studies suggest that germline BAP1 mutations may orchestrate a metastatic ocular melanomas (OM) program and that transmission of deleterious alleles may engender a mixed CM-OM pedigree, which could serve as a clinical marker of constitutive BAP1 loss
We set out to determine if germline BAP1 mutations are more prevalent among (i) OM patients with metastatic disease compared to non-metastatic controls and (ii) CM-OM kindreds relative to CM-non-OM families
Summary
For ocular melanoma (OM), monosomy 3 is one of the most powerful independent predictors of metastasis and negative outcome [1]. Five families with deleterious germline BAP1 mutations were described including several kindreds with both ocular and cutaneous melanoma (CM) [3,4,5]. 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
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