An Important New Paper on Mesotheliomas: “Germline Mutation of Bap1 Accelerates Development of
A June 13, 2014 paper by Dr. Joseph Testa and colleagues expands the ongoing investigation into the relationships among mesothelioma, asbestos fibers, pleural and peritoneal exposures, and the BAP1 mutation (both germline and somatic mutations are under investigation). The research involves creation of a line of “knockout” mice with the BAP1 mutation, and then monitoring mice with and without the mutation for development of mesothelioma (and other cancers) after peritoneal injections of crocidolite asbestos. The paper is online and titled as follows: Joseph R. Testa, et al, Germline Mutation of Bap1 Accelerates Development of Asbestos-Induced Malignant Mesothelioma, Cancer Res June 13, 2014, OnlineFirstJune 13, 2014; doi:10.1158/0008-5472.CAN-14-1328.
An overall conclusion is that crocidolite asbestos exposure – plus the BAP1 mutation – accelerates the development of mesothelioma in the knockout mice with the BAP1 mutation. The authors also report observing zero mesotheliomas among mice that were given the mutation, but were not injected with crocidolite fibers. Various other questions and issues are raised by the ongoing research and the paper.
Numerous constituencies could and should be carefully monitoring studies of this sort, asking the right questions, and designing and paying for other related studies. The constituencies that could and should be actively involved in such efforts include asbestos bankruptcy trusts and trustees, futures representative, expert witnesses, counsel for asbestos plaintiffs and defendants, directors of and officers of defendant companies and insurance and reinsurance companies, and lawyers involved in insurance battles, for either side. However, the unfortunate reality is that most of the members of those constituencies are paying little or no attention to the ongoing revolution in molecular investigation into disease causation, and its implications for toxic tort litigation involving asbestos and other substances.
The full abstract is pasted below:
Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germline inactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers, are not known. To address these questions experimentally, we generated a Bap1+/- knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1+/- mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than WT littermates (73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1+/- mice compared to WT animals (median survival, 43 weeks versus 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1+/- mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1+/- mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in wild-type mice, mesotheliomas from Bap1+/- mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1+/- mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1+/- mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.”