Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma1, and because mesothelioma clustering is observed in some families1, we searched for genetic predisposing factors.,We discovered germline mutations in BAP1 (BRCA1-associated protein 1) in two families with a high incidence of mesothelioma.,Somatic alterations affecting BAP1 were observed in familial mesotheliomas, indicating biallelic inactivation.,Besides mesothelioma, some BAP1 mutation carriers developed uveal melanoma.,Germline BAP1 mutations were also found in two of 26 sporadic mesotheliomas: both patients with mutant BAP1 were previously diagnosed with uveal melanoma.,Truncating mutations and aberrant BAP1 expression were common in sporadic mesotheliomas without germline mutations.,These results reveal a BAP1-related cancer syndrome characterized by mesothelioma and uveal melanoma.,We hypothesize that other cancers may also be involved, and that mesothelioma predominates upon asbestos exposure.,These findings will help identify individuals at high risk of mesothelioma who could be targeted for early intervention.
Activating mutations in BRAF kinase are common in melanomas.,Clinical trials with PLX4032, the mutant-BRAF inhibitor, show promising preliminary results in patients selected for the presence of V600E mutation.,However, activating V600K mutation is the other most common mutation, yet patients with this variant are currently excluded from the PLX4032 trials.,Here we present evidence that a patient bearing the BRAF V600K mutation responded remarkably to PLX4032, suggesting that clinical trials should include all patients with activating BRAF V600E/K mutations.