The present study supports the role of BAP1 as a highly sensitive and specific marker for malignant mesothelioma in serous effusions and argues for inclusion of this test in all specimens in which this diagnosis is considered.
The most frequently altered genes in human MM are cyclin-dependent kinase inhibitor 2A (CDKN2A), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1-associated protein 1 (BAP1), and neurofibromatosis 2 (NF2).
PubMed, Embase and the Cochrane Library and reference lists of related articles were searched, and studies that evaluated the utility of BAP1 in MM were included.
We identified BAP1, CDKN2A and NF2 alterations in the cells from MM pleural effusions at a higher frequency than what is typically seen in MM tumours from surgical series.
Our results suggested that, whereas WT BAP1 suppresses MM cell proliferation and restores cell survival after IR damage, some mutant BAP1 may also moderately retain these functions.
In the context of a mesothelial proliferation, the finding of homozygous deletion of p16 by FISH or loss of BAP1 by immunohistochemistry is, thus far, 100% specific for malignant mesothelioma.
While homozygous CKO of <i>Bap1, Cdkn2a</i>, or <i>Nf2</i> alone gave rise to few or no malignant mesotheliomas, inactivation of <i>Bap1</i> cooperated with loss of either <i>Nf2</i> or <i>Cdkn2a</i> to drive development of malignant mesothelioma in approximately 20% of double-CKO mice, and a high incidence (22/26, 85%) of malignant mesotheliomas was observed in <i>Bap1;Nf2;Cdkn2a</i> (triple)-CKO mice.
Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand).
In the distinction of malignant mesothelioma from benign mesothelial proliferations, immunohistochemical loss of BAP1, the protein expressed by the BAP1 gene, has proven highly specific for malignant mesothelioma.
IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1.
BAP1 loss and high EZH2 expression were highly specific to malignant mesothelioma in differentiating it from benign mesothelial proliferations, and the combination of these two markers improved the diagnostic accuracy.
Diagnostic value of BRCA1-associated protein-1, glucose transporter-1 and desmin expression in the discrimination between reactive mesothelial proliferation and malignant mesothelioma in tissues and effusions.