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.
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.
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.
Nevertheless, this study strengthens the suspicion that, next to germline BAP1 alterations, other genetic factors might predispose families to the development of MM.
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).
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.
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).
The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population.
Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma.
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.