34 research outputs found
Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma
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
Integrative molecular characterization of malignant pleural mesothelioma
Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expresssion of the immune-checkpoint gene VISTA in epithelioid MPM