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"Until recently, the combination of pemetrexed and cisplatin was the only approved first-line therapy, yielding a median overall survival (OS) of 12.1 months.2 Nivolumab plus ipilimumab was approved recently as initial treatment for malignant pleural mesothelioma (MPM) on the basis of a phase 3 clinical trial that resulted in a median OS of 18.1 months.3 4 There are no approved therapies for patients with tumor relapse after first-line therapies.Risk factors in developing mesothelioma include exposure to asbestos5 and other carcinogenic fibers such as erionite,6 and previous radiation therapy.7 8 Studies of familial clusters of mesothelioma have revealed genetic predisposition to develop MM.9 10 Recent work has identified germline mutations in BAP1 that can predispose to mesothelioma11 12 and other cancers such as uveal and cutaneous melanoma, basal cell carcinoma, meningioma, and renal cell cancers.13 14 We previously identified deleterious germline mutations in 12% of 241 consecutive patients with MM who enrolled on a prospective natural history study, with BAP1 being the most frequent germline mutation.15
BAP1 was also recurrently inactivated at the somatic level, suggesting BAP1 variants undergoing positive selection in the context of the classic “two-hit” model.BAP1, a nuclear deubiquitylase, was initially discovered as an interaction partner of the tumor suppressor BRCA1.16 Subsequent studies revealed that BAP1 binds to BARD1, which, in turn, binds to BRCA1, forming the BRCA1-BARD1-BAP1 complex that is crucial for the homologous recombination (HR)–mediated repair of DNA double-strand breaks (DSBs).17 PARP enzymes play a major role in DNA single-strand break repair and base excision repair pathways."