How Do Genetics Impact Mesothelioma Incidence?
One of the biggest questions facing researchers is why some people exposed to asbestos develop mesothelioma, but most do not. While exposure levels and the duration of exposure play significant roles, researchers have found some people are just more susceptible to toxic asbestos fibers.
For example, mesothelioma cases have been reported in people with only a one-time exposure to asbestos. In these cases, researchers believe there are genetic factors that make a person more prone to developing mesothelioma.
The most well-known mesothelioma genetic risk factor is BAP1, a tumor-suppressor gene. Several studies show mutations of BAP1 increase the risk of developing mesothelioma.
Unlocking the connection between genetic risk factors of mesothelioma helps researchers develop prevention techniques and more effective treatment options.Learn More About the Causes of Mesothelioma
BAP1 Gene and Mesothelioma
In a 2011 study conducted at the University of Hawaii Cancer Center and Fox Chase Cancer Center in Philadelphia, researchers discovered people who carry a mutation in a gene called BAP1 are susceptible to developing mesothelioma.
The gene is located on the short arm of chromosome three. The study evaluated two U.S. families with high incidences of mesothelioma and the mutation of the BAP1 gene. Researchers noticed every family member who had contracted the disease also carried the BAP1 mutation.
Further research shows the BAP1 mutation is found in an estimated 70% of mesothelioma cases, making the gene a potential target for prevention, early detection and treatment. Only 20% of cancers overall are associated with the BAP1 mutation.
The BAP1 gene regulates a channel that moves calcium inside cells. When the gene is damaged or mutated, calcium levels drop, making it more likely to become malignant when exposed to carcinogens such as asbestos.
Can Mesothelioma Be Inherited?
Asbestos exposure is the No. 1 cause of mesothelioma. However, a person can be born with a mutated BAP1 gene, which is often inherited. The BAP1 mutation can also develop later in life as cells become malignant.
People with a history of asbestos exposure are more likely to develop mesothelioma if they have damaged or mutated BAP1 genes.
BAP1 Gene as a Screening Tool
The National Cancer Institute opened a clinical trial in March 2019 exploring predisposition to mesothelioma and potential solutions to negate it. NCI senior investigator Dr. Raffit Hassan and his staff are studying BAP1 and other similar-acting genes in the trial.
Hassan believes the study could lead to a regular screening process and routine exams for people with these gene mutations.
“This is an important, long-term study that could have implications not only for a patient, but for family members, too,” Hassan said. “Progress can be made in terms of prevention and early detection.”
If a mutation is not found in someone with asbestosis, for example, it can ease a high-risk individual’s fear of increased susceptibility for mesothelioma and other cancers. And if doctors locate a BAP1 mutation, they can provide a patient with steps to minimize the risk of developing mesothelioma, including avoiding workplace exposures to asbestos.
Testing for BAP1 requires a blood sample. It takes an average of two weeks to get results. A positive result means the gene is mutated, and a negative result means the gene is normal.
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Using Genetics to Treat Mesothelioma
A study published in June 2017 in the journal Nature details why a person with BAP1 mutations becomes more resistant to chemotherapy — a common problem with mesothelioma patients.
Researchers found mesothelioma cells become much more responsive to chemotherapy when BAP1 levels are restored and calcium channels are fixed and stabilized.
“The fixed channels should be able to prevent cancer in people who have inherited the mutation and help treat cancers whose tumor cells have developed mutations,” said Dr. Michele Carbone, director of thoracic oncology at the University of Hawaii Cancer Center.
Dr. Michele Carbone director of thoracic oncology at the University of Hawaii Cancer Center
“You cannot fix something unless you know what is broken. We discovered the first, and so far, only known biological mechanism that makes some people more susceptible. We discovered why and how BAP1 mutations cause cancer.”
Mesothelioma Immunotherapy and Genetics
In July 2018, the National Institutes of Health opened a phase II clinical trial involving the immunotherapy drug Lynparza (olaparib) and its response rate in pleural and peritoneal mesothelioma.
Lynparza is a protein inhibitor and targeted therapy already used effectively with breast and ovarian cancers. It targets the BRCA gene, which is closely related to BAP1.
Researchers are hoping the close relationship in the two genes will allow for similar results in mesothelioma to those in breast and ovarian cancers. The trial is expected to last through 2020.
How Genetics Impact Prognosis
Currently, it is difficult for doctors to predict which mesothelioma patients will live longer than the average. In the future, genetic testing may provide more accurate estimations of how long someone may survive with mesothelioma.
An April 2019 study published in the Proceedings of the National Academy of Sciences showed how genetic mutations of DNA repair genes impact mesothelioma survival. Patients who had a mutation of a DNA suppressor gene survived significantly longer than those without the mutation.
|With Mutation||Without Mutation|
|7.9-year median survival||2.4-year median survival|
|Source: Proceedings of the National Academy of Sciences, 2019|
It seems BAP1 increases the risk of developing mesothelioma, but also improves chances of long-term survival. In the future, this could mean people with the BAP1 gene could receive more aggressive treatment because research shows they respond better than the average patient.
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Other Genetic Biomarkers for Early Detection
Ongoing studies continue to explore the link between gene mutations and cancer. Researchers hope to discover more about what causes tumors to grow, ways to prevent mutations, and what drugs and treatments can prevent the spread of cancer.
Researchers in Belgium studied a family with a strong history of mesothelioma in 2014. Investigators were able to rule out BAP1 as a cause of mesothelioma in this family but identified 11 other possible gene mutations.
The most promising mutation was RBM15. However, the study could not prove RBM15 mutations caused mesothelioma or other cancers in the Belgian family.
Gaining a better understanding of these mutations allows researchers to further personalize treatment. Many of the mutations have been found in other cancers, and drugs that target those mutations already exist.
Dr. Haining Yang at the University of Hawaii Cancer Center is leading research into how variants of a blood protein called High-Mobility Group Box 1 (HMGB1) can be a key for early detection of mesothelioma.
In a June 2016 study published in Clinical Cancer Research, Yang and her team discovered differences in the behaviors of HMGB1 proteins in malignant mesothelioma cells compared to normal mesothelial cells.
Researchers found mesothelioma patients have a hyperacetylated isoform of HMGB1 in their blood, while people with a history of asbestos exposure, not yet diagnosed with cancer, have high amounts of non-acetylated HMGB1.
Although more research with bigger cohorts is needed, the finding is promising for early detection of mesothelioma. Detecting levels of HMGB1 and its isoforms in blood may help recognize populations at high risk.
“We can monitor them and try to detect mesothelioma at an early stage when this cancer is more susceptible to therapy,” Yang said. “That is what we hope to do in the future.”
11 Cited Article Sources
U.S. National Library of Medicine. (2019, May 2). A Trial of Niraparib in BAP1 and Other DNA Damage Response (DDR) Deficient Neoplasms (UF-STO-ETI-001).
Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03207347?term=nct03207347&rank=1
Hassan, R. et al. (2019, April 30). Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.
Retrieved from: https://www.pnas.org/content/early/2019/04/10/1821510116.abstract
U.S. National Library of Medicine. (2019, March 21). Long Term Follow-up of Mesothelioma Patients and Their Family Members With Germline Mutations in BAP1 and Other Genes.
Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03830229?term=NCT03830229&rank=1
Hylebos, M. et al. (2018, June 30). Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma.
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U.S. National Library of Medicine. (2018, June 19). Olaparib in People With Malignant Mesothelioma.
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Barbiero, F. et al. (2018, June 5). Cancer incidence in a cohort of asbestos-exposed workers undergoing health surveillance.
Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/29869702
Broderick, J. (2017, October 17). FDA Approves Olaparib for BRCA+ Breast Cancer.
Retrieved from: https://www.onclive.com/web-exclusives/fda-approves-olaparib-for-brca-breast-cancer
National Cancer Institute. (2017, June 7). Asbestos Exposure and Cancer Risk.
Retrieved from: https://www.cancer.gov/about-cancer/causes-prevention/risk/substances/asbestos/asbestos-fact-sheet
Napolitano, A. et al. (2016, June 15). HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients.
Retrieved from: http://clincancerres.aacrjournals.org/content/22/12/3087
University of Hawaii Cancer Center. (2016, January 13). Possible Discovery of Biomarker for Asbestos Exposure and Mesothelioma.
Retrieved from: http://www.uhcancercenter.org/component/content/article/18-news-releases/422-possible-discovery-of-biomarker-for-asbestos-exposure-and-mesothelioma
- National Institutes of Health. (2011, August 28). NIH-funded researchers discover genetic link to mesothelioma. Retrieved from: https://www.nih.gov/news-events/news-releases/nih-funded-researchers-discover-genetic-link-mesothelioma
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Last Modified July 11, 2019