Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop the tumor. Germline mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma. We hypothesized that other genes involved in hereditary cancer syndromes could be responsible for the inherited mesothelioma predisposition. We investigated the prevalence of germline variants in 94 cancer-predisposing genes in 93 MPM patients with a quantified asbestos exposure. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair. Patients carrying PTVs represented 9.7% of the panel and showed lower asbestos exposure than did all the other patients (p = 0.0015). This suggests that they did not efficiently repair the DNA damage induced by asbestos and leading to carcinogenesis. This study shows that germline variants in several genes may increase MPM susceptibility in the presence of asbestos exposure and may be important for specific treatment.

Inherited loss-of-function mutations in the BAP1 oncosuppressor gene are responsible for an inherited syndrome with predisposition to malignant mesothelioma (MM), uveal and keratinocytic melanoma, and other malignancies. Germline mutations that were inherited in an autosomal dominant fashion were identified in nine families with multiplex MM cases and 25 families with multiple melanoma, renal cell carcinoma, and other tumors. Germline mutations were also identified in sporadic MM cases, suggesting that germline mutations in BAP1 occur frequently. In this article, we report the analysis of BAP1 in five multiplex MM families and in 103 sporadic cases of MM. One family carried a new truncating germline mutation. Using immunohistochemistry, we show that BAP1 is not expressed in tumor tissue, which is in accordance with Knudson's two hits hypothesis. Interestingly, whereas the three individuals who were possibly exposed to asbestos developed MM, the individual who was not exposed developed a different tumor type, that is, mucoepidermoid carcinoma. This finding suggests that the type of carcinogen exposure may be important for the cancer type that is developed by mutation carriers. On the contrary, the other families or the 103 sporadic patients did not show germline mutations in BAP1. Our data show that BAP1 mutations are very rare in patients with sporadic MM, and we report a new BAP1 mutation, extend the cancer types associated with these mutations, and suggest the existence of other yet unknown genes in the pathogenesis of familial MM.

41BAP1 germline mutations predispose to a cancer predisposition syndrome that includes 42 mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence 43 suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we 44 studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for 45BAP1and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF 46 and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. 47In two out of six families with both mesothelioma and melanoma we identified either a germline 48 nonsense mutation (c.1153C>T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation 49 (c.301G>T, p.Gly101Trp) in CDKN2A. 50Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and 51 mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that 52 these tumors share key steps that drive carcinogenesis and that other genes may be involved in 53 inherited predisposition to malignant mesothelioma and melanoma.