Study Reveals Gene-Environment Interaction That Increases The Risk Of Mesothelioma

PHILADELPHIA (February 22, 2016) – Mutations in BAP1 are associated with a wide spectrum of tumor types, but the role of this gene in cancer has been controversial. In a new study, Fox Chase Cancer Center – Temple Health researchers provide conclusive evidence that Bap1 is a bona fide tumor suppressor gene that strongly interacts with environmental factors to control the risk of developing malignant mesothelioma and other cancers. The findings, reported February 22nd in Cancer Research, shed light on the recently recognized BAP1 cancer syndrome, paving the way for new early detection and therapeutic strategies for a range of highly aggressive, hard-to-treat cancers.

Joseph Testa, PhD, FACMG
Joseph Testa, PhD, FACMG

“One of the biggest questions facing mesothelioma researchers is why some individuals exposed to asbestos develop cancer, while others do not,” said senior study author Joseph Testa, PhD, FACMG, professor and Carol and Kenneth E. Weg Chair of Human Genetics at Fox Chase. “Our study suggests that inherited BAP1 mutations significantly increase the chance that exposure to these toxic mineral fibers will ultimately trigger the development of mesothelioma.”

Recent studies in humans have shown that BAP1 mutations are associated with a higher risk of developing certain types of eye and skin tumors as well as malignant mesothelioma—an aggressive, treatment-resistant cancer that forms in the lining of the chest or abdomen, typically in response to asbestos exposure. However, other studies have shown that BAP1 mutations decrease cell proliferation as well as the formation and spread of tumors. These contradictory findings have left scientists perplexed about the role that BAP1 plays in cancer. Moreover, it has not been clear if naturally occurring BAP1 mutations influence the risk of developing these cancers following exposure to environmental factors.

To address these questions, Testa and his team generated three different mouse models with Bap1 mutations, including two models with mutations identical to naturally occurring genetic changes seen in families with multiple cases of mesothelioma. They found evidence of malignant tumors in 58 percent of these mice, compared with only 9 percent of mice lacking Bap1 mutations. All three mouse models showed an increased incidence and similar spectrum of tumor types affecting the ovaries, lungs, skin and mammary glands. Similar to humans with inherited BAP1 mutations, two of the mutant mice developed malignant mesothelioma.

The researchers next injected asbestos fibers into the mice to study how their genetic background would interact with carcinogen exposure to influence the risk of developing malignant mesothelioma. They found that Bap1 mutations more than doubled the risk of developing this type of cancer in response to asbestos exposure. These tumors formed in more than 70 percent of mutated mice, compared with 35 percent of normal mice. Bap1 mutations also resulted in larger and more aggressive tumors that were more likely to spread to the pancreas, liver and intestines.

“These findings firmly establish in three independent experimental models that Bap1 is a bona fide tumor susceptibility gene,” Testa said. “Moreover, our study demonstrates that BAP1 mutations strongly interact with environmental factors to increase the risk of developing malignant mesothelioma.”

In future studies, the new mouse models could serve as valuable tools for examining the role of gene-environment interactions in the formation and spread of malignant tumors. For example, it would be possible to use these mice to determine how exposure to ultraviolet light interacts with Bap1 mutations to increase the risk of certain forms of skin cancer. Ultimately, these studies could lead to a better understanding of melanoma, malignant mesothelioma and other cancers, paving the way for the development of novel early detection and treatment strategies.

“We anticipate that as more studies uncover the precise mechanisms by which BAP1 mutations cause mesothelioma and melanomas, specific preventive and therapeutic approaches for these malignancies will be developed,” Testa said. “For patients, this could eventually translate into earlier diagnosis and a much better prognosis for highly aggressive cancers that are resistant to currently available therapies.”

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence six consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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