The clinical standard treatment for patients with malignant pleural mesothelioma (MPM) includes a cisplatin-based chemotherapy, leading to reduction of tumor size in only a minority of patients. Predicting response to chemotherapy in MPM patients using a genetic marker would therefore enable patient stratification. In this retrospective biomarker study, eligible patients had resectable MPM, measurable disease, and available primary MPM tissue. All patients underwent first-line treatment with

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... platin and pemetrexed followed by surgery. Thorough molecular analysis was performed (whole exome and targeted deep sequencing, copy number analyses), and also mechanistic in vitro data (viability assays, Western blots, immunoprecipitation) using mesothelioma cell lines with and without siRNA-mediated BAP1 knodckdown was provided. In a training cohort of MPM patients (n=28), mutations or deletions of BAP1 each predicted resistance to chemotherapy in primary MPM patients. The negative predictive value of BAP1 loss in MPM patients was confirmed by amplicon sequencing and copy number array technology in an independent test cohort (n=39). Preliminary mechanistic studies using siRNA-based knockdown of BAP1 in MPM cell culture models along with immunoprecipitation assays confirmed chemoresistance in vitro, possibly through inhibition of apoptosis and transcriptional regulation of the BAP1/HCF1/E2F1 axis. Alterations in BAP1 in MPM were a negative predictor for response to chemotherapy and could possibly be used as a companion biomarker for treatment decision.