Loss of expression of BAP1 predicts longer survival in mesothelioma.

BRCA1-associated protein 1 (BAP1) is a tumour suppressor gene frequently inactivated in mesothelioma, rarely also in association with germline mutation. BAP1 mutations have been associated with improved prognosis and distinct clinicopathological features. We sought to determine the clinicopathological significance of BAP1 immunohistochemistry (IHC) in mesothelioma.We performed IHC on a tissue microarray (TMA) cohort comprising all available thoracic mesotheliomas encountered during the period 1991-2014 at our institution (n = 229). All cases were independently reviewed to confirm the diagnosis and subclassify as epithelioid, sarcomatoid or biphasic. The median age at diagnosis was 72 years; 188 (82.1%) were male; 120 (52.4%) were epithelioid (median survival 13.0 months), 67 (29.3%) sarcomatoid (median survival 5.6 months) and 42 (18.3%) biphasic (median survival 10.6 months). 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. There was complete interobserver concordance for BAP1 IHC status. BAP1 loss was strongly associated with younger age at onset (p < 0.01) and epithelioid differentiation (p < 0.01). BAP1 loss predicted an improved median survival of 16.11 months (95% CI 12.16-20.06) versus 6.34 months (95% CI 5.34-7.34), p < 0.01. In a multivariate model including age, gender and histological type, BAP1 loss, younger age and epithelioid differentiation remained protective (all p < 0.01).If our results are confirmed by others, BAP1 IHC may have a role to predict prolonged survival or triage formal genetic testing for germline BAP1 mutation in patients presenting with mesothelioma.