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 to 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 to 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.

Diagnostic and prognostic biomarkers for malignant mesothelioma: an update

“…This hypothesis was supported by the findings in germline BAP1 heterozygous mice, where minimal exposure to carcinogenic fibers highly increased the risk of mesothelioma (15).…”

“…However, additional factors including SV40 infection (11)(12)(13), exposure to radiation, especially high doses radiotherapy of lymphoma and other chest malignancies (1), may also cause mesothelioma, possibly in concert with asbestos (14,15).…”

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

“…The existing literature, however, supports the hypothesis that monoallelic losses of these genes are of biological relevance: (i) In mice, monoallelic losses of Bap1 alter asbestos-induced peritoneal inflammatory response (42) and induce ccRCC in the presence of a coexisting Vhl deficiency (43). (ii) In chronic lymphocytic leukemia, SETD2 alterations are very often monoallelic, and epigenetic inactivation of the wild-type allele is absent.…”

Mesothelioma: recent highlights

“…Subsequently, we discovered that germline BAP1 truncating mutations caused a very high incidence of mesothelioma in some US families in the absence of occupational asbestos exposure (28). Moreover, using a BAP1 +/− mouse model, we demonstrated that mice carrying germline BAP1 mutations develop mesothelioma following exposure to very low doses of asbestos that rarely cause mesotheliomas in wild-type mice (29). Our data, confirmed and expanded by others, showed that germline BAP1 mutations are also associated with uveal melanoma (28) and other malignancies (30-37).…”