BAP1 Identified as a Tumor Suppressor Gene, Increasing Mesothelioma Risk

Investigators think they have identified the gene-environment interaction that increases the risk of mesothelioma, an aggressive cancer that forms in the lining of the chest or abdomen, typically in response to asbestos exposure. Until now, it has been treatment-resistant, but a new discovery may change that.

In a study published February 19, 2016, in Cancer Research, investigators at Fox Chase Cancer Center in Philadelphia report that BRCA1-associated protein-1 (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 shed light on the recently recognized BAP1 cancer syndrome, an inherited cancer syndrome caused by BAP1 germline mutations, with high incidence of mesothelioma, uveal melanoma, and other cancers. They also pave the way for new early detection and therapeutic strategies for a range of highly aggressive, difficult-to-treat cancers.

“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 of Human Genetics at Fox Chase, in a news release. “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.”

BAP1 mutations are associated with a higher risk of developing certain types of eye and skin tumors as well as malignant mesothelioma.  In this current study, investigators tested 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% of these mice, compared with only 9% 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% of mutated mice, compared with 35% 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.

“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.”