Germline mutations in BAP1 predispose to melanocytic tumors

Abstract

Common acquired melanocytic nevi are benign neoplasms that are composed of small uniform melanocytes and typically present as flat or slightly elevated, pigmented lesions on the skin. We describe two families with a new autosomal dominant syndrome characterized by multiple skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected patients developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of the BAP1 gene. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histologic similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

“…Accumulative evidence has reported the diverse roles of ubiquitination in different biological activities and its great importance in the pathogenesis of various cancers, including melanoma 11. For example, the inactivating somatic mutations of BAP1 , a nuclear ubiquitin carboxyl‐terminal hydrolase (UCH), were frequently detected in metastasizing uveal melanomas, and melanoma cell with BAP1 gene deficiency grew as multi‐cellular non‐adherent spheroids with rounded epithelioid morphology, paralleled with increased metastatic capacity 26, 27. In addition, the mutation of ubiquitin ligase FBXW7 resulted in hyper‐activation of Notch1 signalling and subsequent sustained proliferation of melanoma cells by up‐regulation of cell‐cycle mediators 28, 29, 30.…”

Deubiquitylases From Genes to Organism

“…Somatic inactivating mutations have been found at high incidence in uveal melanomas, clear cell renal carcinoma, and pleural malignant mesotheliomas (1,82,86). Germline mutations have been linked to a tumor predisposition syndrome for melanocytic tumors and mesothelioma (252,274). BAP1 gene deletion in mice is embryonically lethal, but conditional knockout mice develop a myeloid disorder resembling chronic myelomonocytic leukemia (CMML) (57).…”

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.…”