Germline BAP1 Inactivation Is Preferentially Associated with Metastatic Ocular Melanoma and Cutaneous-Ocular Melanoma Families

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.

Mesothelioma families without inheritance of a BAP1 predisposing mutation

“…We cannot exclude large deletions of BAP1 that are undetectable by Sanger sequencing [3,9,11,19]. However, large deletions of BAP1 have never been detected in germline configuration in families either with multiple MM [3,9,11,[32][33][34][35][36][37] or without MM [26,28,29]. The loss of nuclear BAP1 immunostaining suggests that these tumors may harbor somatic alterations of the BAP1 gene, a frequent event in sporadic epithelial MM [21,24,26,27].…”

Molecular pathology of uveal melanoma

“…Interestingly, germline BAP1 mutations have been described in families with a high risk for hereditary cancer and a novel 'BAP1 cancer syndrome' including UM has been since been described by several groups. [142][143][144][145][146] Besides BAP1, other genes are likely to be involved in the metastatic process, as indicated by our aSNP and whole exome sequencing of clinically and cytogenetically well-defined cohorts of UM with long-term follow-up (Lake et al, in press). 147 …”

Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma

“…[11][12][13] Inactivating somatic and germline BAP1 mutations have been identified in a variety of cancers, including malignant pleural mesotheliomas, cutaneous melanoma, atypical cutaneous melanocytic tumors, meningioma, lung adenocarcinoma, and renal cell carcinoma. [14][15][16][17][18][19] The number of reported cancer-prone families with germline BAP1 mutations is rising and suggesting a BAP1 cancer syndrome. However, the prevalence of germline BAP1 mutations in uveal melanoma patients is low compared with BAP1 mutations of somatic origin.…”

“…However, the prevalence of germline BAP1 mutations in uveal melanoma patients is low compared with BAP1 mutations of somatic origin. 8,16,20 Although somatic mutations in BAP1 are highly prevalent in metastasizing primary uveal melanoma, the role of BAP1 in the progression of uveal melanoma towards metastatic disease requires further investigation.…”