Asbestos Exposure May Be Required to Cause Mesothelioma—Even in Patients with Risk-Increasing Mutation

While mutations in the BAP1 gene are known to increase risk for mesothelioma, new findings by Fox Chase researcher Joseph R. Testa, PhD, and colleagues indicate that asbestos exposure is also generally necessary to develop the disease.

In a study published in the August 15 issue of Cancer Research, the team exposed mice with and without BAP1 mutations to asbestos, and they also followed a group of unexposed mutated mice to see if they developed any cancers.

By the end of the study, 73 percent of mutated mice exposed to asbestos had developed mesothelioma, compared to only 32 percent of mice without a BAP1 mutation. However, none of the unexposed mice with BAP1 mutations showed signs of mesothelioma after 110 weeks of follow-up. “To get mesothelioma, having a BAP1 mutation doesn’t appear to be enough,” says Testa, co-leader of Fox Chase’s cancer biology program and lead author on the study. “Our studies suggest that you generally need to be exposed to asbestos as well.”

Mesotheliomas in BAP1-mutated mice appeared sooner and were more aggressive than those in non-mutant mice. The tumors from mutant mice typically lost the second copy of BAP1, leading to complete inactivation of BAP1, and the resulting tumors became more invasive and showed increased growth properties. They also showed less activity in a protein encoded by Rb, a gene commonly mutated or deleted in cancer, suggesting that it had been blocked as a result of the inactivation of BAP1.

The level of asbestos exposure used in the study was sufficient to induce mesothelioma or other asbestos-related deaths in all mutated mice, whereas 20 percent of mice without BAP1 mutations were still alive at the conclusion of the study. This suggests that mutation carriers may be susceptible to tumor development at exposure levels that may not always be sufficient to cause cancer when a BAP1 mutation is not present.

Although mutated mice that were not exposed to asbestos did not develop mesothelioma during the study, Testa says, “we can’t say definitively yet that genetics alone can’t cause some cases of mesothelioma.”

Joseph R. Testa, PhD

Joseph R. Testa, PhD

Co-authors on the study include Jinfei Xu, PhD, Yuwaraj Kadariya, MD, PhD, Mitchell Cheung, PhD, Jianming Pei, MD, Jacqueline Talarchek, Eleonora Sementino, MS, Yinfei Tan, PhD, Craig Menges, PhD, Kathy Cai, MD, PhD, Samuel Litwin, PhD, Hongzhuang Peng, PhD, Jayashree Karar, PhD, and Frank J. Rauscher, PhD.