Functional assessments in BAP1 inactivated, BAP1 wild-type and BAP1 catalytically dead-expressing NCI-H226 and QR mesothelioma cell lines confirmed alteration of these pathways and demonstrated that BAP1 deubiquitinase activity was mandatory to maintain these phenotypes.
Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes.
On cytology/cell blocks, benign mesothelial cells were invariably positive for BAP1, whereas 64% of mesotheliomas showed loss of protein; all 6 cases showing BAP1 negativity were associated with histological diagnosis of BAP1-negative mesothelioma.
This suggests that besides the exposure to asbestos other currently unknown genetic or epigenetic factors may be responsible for the high incidence of mesothelioma in BAP1-unmutated families.
BAP1 mutation has been linked to non-asbestos induced familial mesotheliomas, which usually belong to the long survivor group and BAP1 is most probably functioning differently than in sporadic cases.
BAP1 immunohistochemistry and p16 fluorescence in situ hybridization (FISH) have recently been reported as reliable markers of malignancy in biopsies of mesothelioma.
Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.
Loss of BAP1 has recently been described as a highly specific marker for distinguishing malignant mesotheliomas (MM) from benign mesothelial proliferations (BMP).
We conclude that: (1) BAP1 immunohistochemistry is relatively insensitive in the context of sarcomatous and desmoplastic mesotheliomas, but as a matter of time and cost efficiency may nonetheless be a useful first approach to the problem; (2) deletion of p16 by FISH is considerably more sensitive, but there remain a proportion of cases in which p16 is not deleted; (3) a small improvement in sensitivity can be achieved by using both markers; (4) in the context of a spindle cell malignant tumor in the pleura or peritoneum, which morphologically might be a metastatic sarcomatoid carcinoma or a mesothelioma, the finding of BAP1 loss favors mesothelioma, but p16 FISH cannot be used to separate sarcomatous mesotheliomas from sarcomatoid carcinomas.
Remarkable findings included the discovery of germline and somatic mutations of BRCA1 associated protein-1 (BAP1) in patients, and the genome-wide characterization of pathways altered in mesothelioma that could be potentially exploited to design novel therapeutic approaches.
BAP1 loss was detected in 61/88 (69%) tissues and in 20/30 (67%) cytology samples from mesothelioma with a specificity of 100% for both sampling methods.
To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPMs.
In line with the screen results, primary mesothelioma (BAP1+/-) overexpressing BAP1C91A (catalytically dead mutant) were more resistant to RNR inhibition, while BAP1 knockdown in the BAP1-proficient cell lines rescued the cells from their vulnerability to RNR depletion.
23% of mesothelioma tumor specimens have a mutation in the BRCA1-associated protein 1 (BAP1) gene and germline BAP1 mutations predispose to malignant pleural mesothelioma (MPM).