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Is Mesothelioma Genetic?
Asbestos is the only proven cause of mesothelioma, but not everyone exposed to asbestos develops this cancer. In fact, most exposed people aren’t affected.
This fact is why researchers investigate whether mesothelioma is hereditary. If so, then some people would have genetic dispositions to asbestos-caused cancers.
However, there isn’t any irrefutable scientific link between a person’s genes and their likelihood to get this disease. There’s no medical reason explaining why one person gets this cancer yet another doesn’t.
There is genetic science behind this cancer and value in continuing genetic research.
Benefits of Mesothelioma Genetic Testing and Research
Asbestos causes mesothelioma by piercing into tissue and altering a cell’s DNA. This disruption of genetic balance leads to cells duplicating, living longer than they should, and forming clumps known as tumors. It all starts with the sharp edge of an asbestos fiber disturbing a cell’s genetic equilibrium.
This is why genetics testing is useful for people with mesothelioma — and for doctors trying to solve the riddle of this cancer. No two people will have the exact same mesothelioma, especially at the molecular level.
Dr. Ezra Cohen, an oncologist at University of California San Diego Health, treats pleural mesothelioma. He said genetic testing and research on a patient-by-patient level is essential. It can provide information on genetic mutations, expression and the tumor microenvironment.
“This is an overriding principle in cancer in general, and especially for mesothelioma,” Dr. Cohen said. “The more we know about a disease, the better-equipped we are to deal with it.”
For instance, each person will have different levels of gene and protein expression on the diseased cells and tumors. Some therapies, such as immunotherapy, specifically target these genes and proteins.
Measuring a person’s gene and protein expression may lead to an individualized treatment regimen. This can be effective in controlling each patient’s unique cancer. Gene analysis can also help doctors provide a more precise prognosis.
Get Connected with Clinical Trials
Improve your prognosis and the likelihood of beating mesothelioma through clinical trials.
One of the best ways to improve your prognosis and the likelihood of beating mesothelioma is through clinical trials.
Clinical trials can provide:
- Exclusive access to promising new procedures
- One-on-one care from leading mesothelioma specialists
- Alternative options for patients who have exhausted traditional treatments
Mesothelioma Genes and Proteins
Genes (DNA) create clones of themselves (RNA), and these clones deliver instructions to the cell on how to make necessary proteins. So a mutated gene can lead to an overexpression or underexpression of specific proteins.
Mesothelioma forms when asbestos ruptures the DNA of mesothelial cells. This disturbance can affect proteins involved in controlling mesothelial cell growth, duplication or death. Underexpression of these genes and proteins can lead to rampant cell division.
Damage to a cell’s DNA can also result in cancerous proteins. Overexpression of these proteins and genes causes harm to the body.
Some genes create proteins of the same name. Other genes have a different name than the protein they create.
BAP1 is an important tumor-suppressing gene and protein in our body. It controls cell growth, division and death. The gene can also mutate and become ineffective in stopping mesothelioma.
The loss of BAP1 leads to the overexpression of another gene, EZH2. This genetic imbalance is part of the cell mutation process that results in mesothelioma.
A large percentage of mesothelioma patients are BAP-1 deficient. One study had 70 out of 74 patients (95%) suffer from inactivated BAP-1 genes.
PD-L1 is an immune checkpoint inhibitor protein coded by the CD274 gene. It subdues the immune system by merging with the PD-1 protein receptor on a type of cancer-fighting white blood cell (T-cells).
PD-L1 connects with the PD-1 receptors and deceives T-cells into believing mesothelioma cells are harmless. A lot of immunotherapy drugs focus on stopping the bridge PD-L1 forms with PD-1.
Recent clinical studies have proven immunotherapy effective for people with high PD-L1 expression. In one study, around 38% of mesothelioma patients expressed notable levels of PD-L1.
The U.S. Food and Drug Administration approved Opdivo, the brand name drug for nivolumab, for mesothelioma. Opdivo is a PD-L1 inhibitor immunotherapy drug.
VISTA is an immune system-suppressing protein encoded by the C10orf54 gene. High levels of VISTA expression can subdue T-cells and prevent their activation against cancerous mesothelial cells.
According to a study in Modern Pathology, VISTA was expressed in 85% of 319 analyzed mesothelioma cases.
B7 is a protein found on cancer cells such as mesothelioma. The gene CD80 encodes this protein, which helps the disease thrive in a similar manner as PD-L1.
B7 connects with the T-cell receptor CTLA-4. When binding occurs, the B7 protein restrains the immune system’s response to mesothelioma.
The FDA approved Yervoy, the brand name for ipilimumab, for mesothelioma. It’s another checkpoint inhibitor drug. It blocks the attachment of B7 to CTLA-4.
The Emergence of Gene Therapy for Mesothelioma
Mesothelioma gene therapy has become one of the leading innovative treatments for mesothelioma. There are four types:
- Blocking cancerous genes and proteins (gene inhibition)
- Adding cancer-fighting genes to the body (gene addition)
- Replacing damaged genes (gene replacement)
- Fixing damaged and mutant mesothelioma genes (gene editing)
As an example of the former, the drug tazemetostat blocks the EZH2 gene often overexpressed in mesothelioma. A recent phase 2 clinical trial testing tazemetostat resulted in a 64% response rate. Response rate means the treatment at least stalled the growth of their cancer.
TR002 is an example of adding a gene to the body (gene addition). TR002 is a non-active virus that delivers a gene into the disease location. This gene increases the levels of interferon alpha-2b protein, which the body uses to fight diseases. The therapy showed a disease control rate of 87.5%.
Gene Therapy Expert Joins Mesothelioma Guide Podcast
Dr. Daniel Sterman is the director of the Multidisciplinary Pulmonary Oncology Program at New York University Langone Health. He also led a progressed study that combines gene therapy and immunotherapy for pleural mesothelioma. Dr. Sterman joined the Mesothelioma Guide podcast to discuss the study and his efforts to advance gene therapy for mesothelioma.
“Many immunotherapies are drugs administered intravenously into the body,” Sterman said. “… There is a blockade in the tumor, and these drugs try to unleash that blockade.”
Half of the 300 enrollees received the experimental treatment: an adenovirus-delivered Interferon Alpha-2B along with chemotherapy (Gemcitabine) and an arthritis pain medication (Celecoxib). The other half received just the chemotherapy drug and pain medicine.
Sterman’s trial, he explained, involved a virus transporting a gene into the location of the mesothelioma. Once the gene reaches the site, the tumors produce interferon-alpha. The production of this causes an immune system reaction.
“We are injecting a cold virus into the chest cavity of patients with mesothelioma,” Sterman said. This cold virus has been modified so that it can’t replicate itself. It also can’t cause the common cold.”
Inhalable Gene Therapy for Mesothelioma and Lung Cancer
Researchers in Japan created an inhalable gene therapy: a combination of a gene therapy and inhalable powder. This unique therapy delivers the treatment into the lung cavity to fight cancer.
The tumor-suppressing gene drug, SFD-p16 and SFD-p53, targets three cell lines associated with the two cancers. Studies in mice showed the use of the inhalable gene therapy controlled cell growth and replication in these lines. The average volume of the tumors in these tests shrank thanks to the unique gene therapy.
p16 and p53 were the genes added. This inhalable gene therapy is another form of gene addition.
Accurate Prognosis with Gene Expression
Doctors can use gene expression arrays to provide patients with an accurate prognosis. These tests examine tissue samples taken from a biopsy. Doctors then cross-check DNA from mesothelioma cells against healthy mesothelial cells.
The arrays help determine which genes are expressed in an individual patient’s disease. Doctors can predict the aggressiveness of a mesothelioma by studying the cells’ gene expression. For example, if a tumor-suppressing gene is damaged, this is a sign of a more aggressive disease.
Doctors can also look for high levels of genes creating immune-suppressing proteins, like PD-L1 and B7. If doctors notice an abnormal amount of mesothelioma-related genes or proteins, they can utilize checkpoint inhibitor drugs to activate the immune system.
“Cancer is a molecular disease, and we want to learn more about it at the molecular level,” Dr. Cohen said. “This can change therapeutic decisions up to 80% of the time.”
The benefits of gene expression for patients include:
- Knowing if they will benefit from surgery
- Possibly using targeted immunotherapy treatment options
- Having a better idea of how they will handle chemotherapy
- Peace of mind that their prognosis is accurate
Gene expression tests help patients avoid undergoing unnecessary treatments. Having an accurate prognosis allows patients and families a greater sense of certainty and comfort.
Mesothelioma specialists and researchers are constantly learning more about the disease at the genetic and molecular level. The best way patients can improve their prognosis is by seeing a specialist. Our team can help you connect with any of the top mesothelioma doctors in the country.
Sources & Author
- Integrative Molecular Characterization of Malignant Pleural Mesothelioma. Cancer Discovery. Retrieved from: https://cancerdiscovery.aacrjournals.org/content/8/12/1548. Accessed: 08/13/2020.
- BAP1 gene. Genetics Home Reference. Retrieved from: https://ghr.nlm.nih.gov/gene/BAP1. Accessed: 08/13/2020.
- How do genes direct the production of proteins? Genetics Home Reference. Retrieved from: https://ghr.nlm.nih.gov/primer/howgeneswork/makingprotein. Accessed: 08/13/2020.
- V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant pleural mesothelioma. Modern Pathology. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/31537897/. Accessed: 08/14/2020.
- VISTA is an immune checkpoint molecule for human T cells. Cancer Research. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979527/. Accessed: 08/14/2020.
- Effects of inhalable gene transfection as a novel gene therapy for non-small cell lung cancer and malignant pleural mesothelioma. Nature. Retrieved from: https://www.nature.com/articles/s41598-022-12624-4. Accessed: 05/26/2022.