Loss of BAP1 function is implicated in the oncogenesis of several types of cancers including uveal, mucosal and some cutaneous melanomas in humans, as well as in mesothelioma.
BAP1 was lost in 46 (87%) mesotheliomas compared with 4 (2%) of 205 other cancers (P < .001), resulting in sensitivity and specificity of 87% and 98%, respectively.
We studied 49 cases of mesothelioma (17 epithelioid mesothelioma, 22 biphasic mesothelioma, and 10 sarcomatoid mesothelioma) and 23 benign mesothelial proliferations using a 5-hmC single immunohistochemical stain, CAM5.2/5-hmC double immunohistochemical stain, and BAP1 immunohistochemistry.
These results suggest that the lack of the tumor suppressor BAP1 may be more specifically involved in the pathogenesis of epithelioid MM rather than non-epithelioid MM, and would be useful for diagnosis of epithelioid-type MM.
These discoveries are: (I) the critical role of chronic inflammation in promoting mesothelioma growth, driven by the release of high mobility group box protein-1 (HMGB1) following asbestos deposition in tissues and its potential role as a biomarker to identify asbestos exposed individuals and mesothelioma patients; (II) the discovery that inherited heterozygous germline mutations of the deubiquitylase BRCA-associated protein 1 (<i>BAP1</i>) cause a high incidence of mesothelioma in some families; and that (III) germline BAP1 mutations lower the threshold of asbestos required to cause mesothelioma in mice, evidence of gene X environment interaction.
Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in non-neoplastic cells) occurred in 106 (46.3%) mesotheliomas.
Caution should be applied when PAX8 expression is used to distinguish mesothelial and serous proliferations, and BAP1 loss may be confirmatory in cases where mesothelioma is favored.
The mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma.
None of the reported biomarkers showed adequate diagnostic accuracy, except for <i>p16</i> [evaluated by fluorescent in situ hybridization (FISH)] and BAP1 (evaluated by IHC), both biomarkers are recommended by the International Mesothelioma Interest Group guidelines for histological and cytological diagnosis.
However, the results of immunohistochemical analysis demonstrated loss of nuclear BAP1 staining in three of six mesotheliomas tested, suggesting that somatic alterations of BAP1 occurred in a subset of tumors from this family.
Consistent with these data, BAP1(+/-) mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice.
Surface components of MM of the pleura showed concordant loss as the invasive tumor suggesting a potential role for BAP1 loss for recognizing so-called early mesothelioma.
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.