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

Oncogene. 2016 Apr 14;35(15):1996-2002. doi: 10.1038/onc.2015.243. Epub 2015 Jun 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Asbestos, Crocidolite / administration & dosage
  • Asbestos, Crocidolite / toxicity*
  • Ascitic Fluid / chemistry
  • Chemokines / analysis
  • Cytokines / analysis
  • Dose-Response Relationship, Drug
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Heterozygote
  • Leukocytes / pathology
  • Macrophages, Peritoneal / classification
  • Macrophages, Peritoneal / physiology
  • Male
  • Mesothelioma / etiology*
  • Mesothelioma / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mineral Fibers / toxicity
  • Peritoneal Neoplasms / etiology*
  • Peritoneal Neoplasms / genetics
  • Peritonitis / etiology
  • Peritonitis / genetics
  • Random Allocation
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / physiology
  • Ubiquitin Thiolesterase / deficiency
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / physiology


  • BAP1 protein, mouse
  • Chemokines
  • Cytokines
  • Mineral Fibers
  • Tumor Suppressor Proteins
  • Asbestos, Crocidolite
  • Ubiquitin Thiolesterase