Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers

Abstract

Objective To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer. Design A total of 53 unrelated UM patients with high risk for hereditary cancer and five additional family members of one proband were studied. Mutational screening was carried out by direct sequencing. Results Of the 53 UM patients studied, a single patient was identified with a germline BAP1 truncating mutation, c. 799 C→T (p.Q267X), which segregated in several family members and was associated with UM and other cancers. Biallelic inactivation of BAP1 and decreased BAP1 expression were identified in the UM, lung adenocarcinoma and meningioma tumours from three family members with this germline BAP1 mutation. Germline BAP1 variants of uncertain significance, likely non-pathogenic, were also identified in two additional UM patients. Conclusion This study reports a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers. The results indicate that BAP1 is the candidate gene in only a small subset of hereditary UM, suggesting the contribution of other candidate genes.

Mesothelioma families without inheritance of a BAP1 predisposing mutation

“…The absence of a germline mutation in coding regions and intron-exon boundaries of BAP1 gene was proven in the normal tissue DNA belonging to one index case (D-II-4) and by excluding single point mutations and small InDels in tumor DNA belonging to the other three index cases (C-II-2, O-III-1, G-II-6). 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].…”

“…BAP1 regulates cell cycle control, target genes transcription, and DNA damage repair [2]. The germline mutation in the BAP1 gene is associated with a hereditary tumor predisposition syndrome (BAP1-TPDS, OMIM#614327) that occurs in family members with several cancer types: MM, uveal/cutaneous melanoma, renal cell carcinoma, basal cell carcinoma and other cancers [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. As of March 2016, forty-six families with multiple cases of MM have been analyzed for BAP1 germline alterations.…”

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).…”

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.…”