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Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma

Abstract

Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1+/− mouse model, we found that, compared with their wild-type littermates, BAP1+/− mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1+/− mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.

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Acknowledgements

This work was supported by National Institute of Health (grant numbers R01CA106567, P01CA114047, P30CA071789 to MC and R01CA160715-0A to HY); the DoD CDMRP PRMRP Career Development Award to HY, and the V Foundation to MC and HY, the P30 CA071789 (UHCC Pathology Shared Resource); the Mesothelioma Applied Research Foundation to HY, the United-4A Cure, the Hawaii Community Foundation to HY, and the University of Hawaii Foundation, which received donations to support mesothelioma research from Honeywell International Inc., to MC.

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Correspondence to M Carbone.

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M Carbone has pending patent applications on BAP1 and provides consultation for mesothelioma expertise and diagnosis. The remaining authors declare no conflicts of interests.

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Napolitano, A., Pellegrini, L., Dey, A. et al. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene 35, 1996–2002 (2016). https://doi.org/10.1038/onc.2015.243

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