Genetic Link Predisposes to Mesothelioma

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An investigation led by scientists at the University of Hawaii Cancer Center, Honolulu, and Fox Chase Cancer Center, Philadelphia has identified germline mutations in the BAP1 gene that predispose individuals to malignant mesothelioma. The research, published online yesterday in Nature Genetics, describes two U.S. families with a high incidence of mesothelioma, as well as other cancers, associated with mutations of the gene BAP1 [1].

Scientists have discovered that individuals who carry a mutation in a gene called BRCA1-associated protein 1 (BAP1) are susceptible to developing two forms of cancer — mesothelioma and melanoma of the eye. When these individuals are exposed to asbestos or similar mineral fibers, their risk of developing mesothelioma, an aggressive cancer of the lining of the chest and abdomen, may be markedly increased.

Mesothelioma tumors are typically associated with asbestos and erionite exposure. Erionite is a naturally occurring mineral fiber similar to asbestos that is found in rock formations and volcanic ash. Deposits have been located in at least 12 states. However, unlike asbestos, erionite is not currently regulated by the U.S. Environmental Protection Agency as one of the six asbestos fibers [2]. Only a small percentage of people exposed to asbestos or erionite actually develop mesothelioma.

Mesothelioma is one of the deadliest forms of cancer, killing approximately 3,000 people each year in the United States, with half of those diagnosed dying within one year. Moreover, rates of new cases of mesothelioma in parts of the world, including Europe and China, have risen steadily over the past decade.

Michele Carbone, M.D., Ph.D., study co-leader and director of the University of Hawaii Cancer Center, said [3]:

This discovery is a first step in understanding the role of the BAP1 gene and its potential utility when screening for mutations in those at high risk. Identifying people at greatest risk for developing mesothelioma, especially those exposed to dangerous levels of asbestos and erionite worldwide, is a task made easier by virtue of this discovery.

Joseph R. Testa, Ph.D., study co-leader and Carol and Kenneth E. Weg chair in Human Genetics at Fox Chase Cancer Center, added [3]:

This is the first study to demonstrate that individual genetic makeup can greatly influence susceptibility to mesothelioma. People exposed to dangerous levels of asbestos or erionite, those with a strong family history of mesothelioma, or those who have been previously diagnosed with a rare tumor of the eye known as uveal melanoma, may benefit from this new discovery.

The researchers focused on two US mesothelioma families — one in Wisconsin and one in Louisiana — in which members were not exposed to asbestos or erionite. Family members developed a number of malignancies, including breast, ovarian, pancreatic and renal cancers, although mesothelioma predominated.

The scientists suspected that mutations in the BAP1 gene might underlie mesothelioma in people with a strong family history of the disease after noticing genetic changes in or near other stretches of DNA where the BAP1 gene is located. Looking more closely at two families with unusually high rates of mesothelioma, they saw that every person who had provided a sample and had developed mesothelioma or melanoma of the eye also carried mutations in the BAP1 gene. Further study led to sequencing the gene in 26 individuals who had developed mesothelioma but did not have a family history of the disease. Tumors from about 25 percent of this group carried mutations in the BAP1 gene, and in two cases the mutations were inherited. Both of the individuals with inherited mutations had previously developed melanoma of the eye.

The researchers hypothesize that when individuals with BAP1 mutations are exposed to asbestos, mesothelioma predominates over melanoma of the eye. Alternatively, the BAP1 mutation alone may be sufficient to cause mesothelioma, providing a cause for tumors that arise spontaneously without previous environmental exposure.

References

1. Testa et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nature Genetics. Published online 2011 Aug 28.
   View abstract
2. Erionite. North Dakota Departement of Health. Accessed 2011 Aug 29.
3. NIH-funded researchers discover genetic link to mesothelioma. NIH News press release. 2011 Aug 28.