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.
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.
While the BAP1-mutated subgroup is similar to diffuse malignant pleural mesotheliomas, the TRAF7-mutated subgroup overlaps genetically with adenomatoid tumors and well-differentiated papillary mesotheliomas, in which recurrent TRAF7 mutations have been described.
Immunocytochemical studies on PF cell blocks allow: (a) to distinguish mesothelioma from reactive mesothelial proliferations (e.g. loss of BAP1 nuclear expression, complemented by the demonstration of p16 deletion using fluorescence in situ hybridization, indicate mesothelioma); (b) to separate mesothelioma from adenocarcinoma (e.g. calretinin, CK 5/6, WT-1 and D2-40 are markers of mesothelioma, whereas CEA, EPCAM, TTF-1, napsin A, and claudin 4 are markers of carcinoma); and (c) to reveal tumor origin in pleural metastases of an unknown primary site (e.g.
Cytologic identification of mesothelioma is particularly challenging, but testing for BAP1 nuclear expression (immunocytochemistry) and p16 deletion (fluorescence in situ hybridization) has greatly improved our diagnostic capabilities.
MSLN is a validated cancer target known to be overexpressed in mesothelioma, ovarian, lung, breast, and pancreatic cancer, with low expression in normal tissue.
Sequential use of BAP1 immunohistochemistry and CDKN2A fluorescence in situ hybridization is specific for diagnosis of mesothelioma, but fluorescence in situ hybridization is both costly and time-consuming.
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.
To explore CAR-T therapy in NSCLC and mesothelioma, second-generation CAR-T cells were constructed targeting mesothelin (MSLN), which is abundant in NSCLC and mesothelioma but is under expressed in normal tissues.
MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue.
The combined examination of the 9p21 deletion and loss of p16 expression is helpful for diagnostic purposes, but because the FISH method is an expensive technique and loss of p16 expression is not specific for mesotheliomas, p16 negativity can guide practitioners to eliminate cases that require further investigation by FISH.
Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression.
Cytologic identification of mesothelioma is particularly challenging, but testing for BAP1 nuclear expression (immunocytochemistry) and p16 deletion (fluorescence in situ hybridization) has greatly improved our diagnostic capabilities.
Immunocytochemical studies on PF cell blocks allow: (a) to distinguish mesothelioma from reactive mesothelial proliferations (e.g. loss of BAP1 nuclear expression, complemented by the demonstration of p16 deletion using fluorescence in situ hybridization, indicate mesothelioma); (b) to separate mesothelioma from adenocarcinoma (e.g. calretinin, CK 5/6, WT-1 and D2-40 are markers of mesothelioma, whereas CEA, EPCAM, TTF-1, napsin A, and claudin 4 are markers of carcinoma); and (c) to reveal tumor origin in pleural metastases of an unknown primary site (e.g.
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.
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.
MSLN, a 40kDa glycoprotein that is overexpressed in many cancers including ovarian and mesotheliomas is suggested to play a role in cell survival, proliferation, tumor progression, and adherence.
Finally, the protein levels of ASXL2, BAP1 and UBE2E enzymes are highly correlated in mesothelioma tumors suggesting the importance of this signaling axis for tumor suppression.