Malignant Mesothelioma, BAP1 Immunohistochemistry, and VEGFA: Does BAP1 Have Potential for Early Diagnosis and Assessment of Prognosis?

Abstract

Malignant mesothelioma (MM) is an aggressive malignancy of the serosal membranes. Early diagnosis and accurate prognostication remain problematic. BAP1 is a tumour suppressor gene commonly mutated in MM. Germline BAP1 mutation has been associated with early onset and less aggressive disease compared with sporadic MM. Sporadic BAP1 mutations are common and are associated with improved survival in MM, contrary to other malignancies. This study investigated the prognostic role of BAP1 in matched cytology and surgical specimens and aimed to investigate the association between BAP1 and the established prognostic marker VEGFA from a cohort of 81 patients. BAP1 mutation was found in 58% of histology and 59% of cytology specimens. Loss of BAP1 expression in both surgical and cytology specimens was significantly associated with poorer survival in a multivariate analysis when controlling for known prognostic indicators. Increased levels of VEGFA in pleural effusions were associated with poor survival. We conclude that the prognostic significance of BAP1 mutations in MM cannot be determined in isolation of other prognostic factors, which may vary between patients. Pathologists should employ caution when commenting on prognostic implications of BAP1 status of MM patients in diagnostic pathology reports, but it may be useful for early diagnosis.

Malignant mesothelioma in situ: diagnostic and clinical considerations

“…We have reported loss of BRCA1-associated protein-1 (BAP1) in some effusions and biopsies of patients without invasive tumour at the time who developed invasive tumour later. 18 Preliminary data from Churg et al have identified molecular alterations of BAP1 and CDKN2A in MIS, both of which have been implicated in the pathogenesis of MM. 16,19 Additionally, the same group studied expression of methylthioadenosine phosphorylase (MTAP) in MIS.…”

“…19 BAP1 is a nuclear deubiquitinase which functions as a tumour suppressor gene, and has been commonly implicated in both diagnosis and prognostication in MM. 18,[23][24][25][26] BAP1 loss has been identified in many tumours, and germline mutation often confers a susceptibility to earlier diagnosis of MM and trends within families. 27 BAP1 has been seen to be highly specific for MM but not lost in all MM cases.…”

“…27 BAP1 has been seen to be highly specific for MM but not lost in all MM cases. 18,25 For this reason it can be useful during the diagnosis of MM vs reactive mesothelial proliferations, with loss of expression favouring a diagnosis of MM. 25 However, the loss of nuclear labelling for BAP1 is observed in only a proportion of MM.…”

Emerging Treatments for Malignant Pleural Mesothelioma: Where Are We Heading?

“…Conversely, BAP1 mutant mesothelioma cell lines resulted significantly less sensitive than BAP1 wild type cells to gemcitabine (59). In addition, the role of somatic BAP1 expression in MPM patients receiving chemotherapy still represents a matter of debate, with retrospective studies showing contradictory evidences (60,61).…”

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“…Spot size is 0.6 mm at 100x (inset 400x) magnification. expression has been reported from various tumor types such as non-small cell lung cancer [8,9], renal cell carcinoma [10][11][12], gall bladder cancer [13], mesothelioma [14,15] and uveal melanoma [16][17][18], and has been linked to poor prognosis in most of them [13,17,19]. In addition, inactivating germline mutations result in the BAP1 tumor predisposition syndrome, associated with a high risk of tumor development [20,21].…”