Gene Increases Predisposition to Asbestos-Linked Cancer

PHILADELPHIA, PA (July 24, 2014)—New research in mice adds to the growing body of evidence that an inherited mutation can increase the risk of developing cancer after exposure to asbestos – but simply having a genetic predisposition does not appear to be enough to induce the disease.

Joseph R. Testa, PhD, Professor and Carol and Kenneth E. Weg Chair of Human Genetics at Fox Chase Cancer Center, and colleagues, recently found that mice were more likely to develop the deadly form of cancer associated with asbestos exposure – known as mesothelioma – if they carried a mutation in a gene known as BAP1, which affects the expression of many other genes.  However, when it comes to mesothelioma, exposure to asbestos carries more weight than genetics – even mice that did not carry BAP1 mutations developed tumors after being exposed to asbestos, while none of the unexposed mice with BAP1 mutations showed signs of mesotheliomas by the end of the study.

“To get mesothelioma, having a BAP1 mutation doesn’t appear to be enough,” says Dr. Testa, who is also Co-Leader of the Cancer Biology Program at Fox Chase and lead author on the study which appears online now and will be in the August 15 print issue of the journal Cancer Research, “Our studies suggest that you generally need to be exposed to asbestos, as well.”

Previous research has linked BAP1 to mesothelioma. A 2011 study co-led by Dr. Testa and Dr. Michele Carbone, MD, PhD, Center Director at the University of Hawaii, tracked two families with many cases of mesothelioma, both of which carried inherited mutations in BAP1. Some family members developed other forms of cancer, as well, notably melanomas located in the eyeball and tumors in the skin, breast, ovaries and kidney, suggesting that inherited BAP1 underlie other cancer types, as well.

None of the members of the two families had been exposed to asbestos occupationally, but there was some asbestos in their homes, as is true for many U.S. homes. Even though health agencies have tried to phase out the use of asbestos – commonly used in building construction, auto parts, pipe insulation, as well as on ships – the disease takes decades to develop, explains Dr. Testa.

In the current study, Dr. Testa and his team at Fox Chase exposed mice with and without BAP1 mutations to asbestos, and they also followed a group of unexposed mutant mice to see if they developed any cancers.  

By the end of the study, 73% of mutated mice exposed to asbestos had developed mesothelioma, compared to only 32% of exposed mice that did not carry any BAP1 mutation. In the mutant mice, the mesotheliomas appeared sooner, and were more aggressive, as well. None of the unexposed mice that carried a BAP1 mutation developed mesothelioma after up to 87 weeks of follow-up, although one was diagnosed with a tumor of breast tissue origin.

Taking a close look at the tumors themselves, the researchers noted that mutant mice showed less activity in a protein encoded by RB, a gene commonly mutated or deleted in cancer, suggesting it had been blocked by BAP1. Interestingly, many tumors from mutated mice lost the second copy of BAP1, and the resulting tumors became very aggressive.

Notably, the level of asbestos exposure used was sufficient enough to induce mesothelioma or other asbestos-related deaths in all mutated mice, whereas 20% of mice without mutation of BAP1 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.

These findings should not overly alarm people with a family history of cancer, Dr. Testa cautions. Some families with BAP1 mutations have not developed any mesotheliomas, and generally only a small fraction of people exposed to asbestos develop mesothelioma. Furthermore, he notes that inherited BAP1 mutations are “exceedingly rare in the general population and probably occur in less than 3% of non-familial (sporadic) mesotheliomas.  But given how rarely people develop mesothelioma after exposure to asbestos, families with multiple cases of the disease have a good chance of carrying mutations in BAP1 and should be tested for that possibility.”

Fortunately, people who suspect they may be carriers can be tested for a BAP1 mutation at several labs throughout the country, including Dr. Testa’s at Fox Chase. “If they don’t have the mutation, they don’t have to worry more than the average person,” he says. “But if they do, they can take precautions such as getting regular pulmonary, eye and skin examinations and scans to identify the tumors in their earliest stage, when treatment is most effective.  Some cancer centers also offer experimental blood tests that may help in the early detection of mesothelioma.”

Although mutated mice that were not exposed to asbestos did not develop mesothelioma during the study, Dr. Testa admits that they could eventually show signs of the disease. “We can’t say definitively yet that genetics alone can’t cause some cases of mesothelioma.”

Ultimately, says Dr. Testa, the story of BAP1 and mesothelioma originated in Philadelphia. In 1998, after many workers in the area were exposed to asbestos at the Philadelphia Navy Yard and elsewhere, the BAP1 gene was discovered by Frank J. Rauscher, III, PhD, Professor of the Gene Expression and Regulation Program and Deputy Director for Basic Research at the Wistar Institute Cancer Center.  Today, Drs. Testa and Rauscher are working together to understand how asbestos and BAP1 work synergistically to induce cancer.

“Although defense lawyers representing companies that used asbestos may try to argue that people develop mesotheliomas because of their genetics, we cannot say that it’s just from bad genes,” says Dr. Testa. “With regard to risk, I often think that mesothelioma is like heart disease – a family history of high cholesterol may predispose you to heart problems, but other factors such as poor diet and sedentary life style can act synergistically to enhance that disease risk.”

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