Mesothelioma Genetic Testing, Gene Therapy and Gene Expression
Is there a genetic link to how a person responds to a specific type of treatment for mesothelioma? Research continues in mesothelioma genetic testing, which could help specialists determine a plan for treatment.
Written by Jenna Campagna, RN
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Is Mesothelioma Genetic?
Asbestos is the only proven cause of mesothelioma, but not everyone exposed to asbestos later develops this cancer. In fact, a large majority of exposed people aren’t affected by the disease.
This fact is why researchers investigate whether mesothelioma is hereditary. If so, then some people would have genetic dispositions to asbestos-caused cancers like mesothelioma.
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 person doesn’t.
There is genetic science behind this cancer and value in continuing to research mesothelioma genetics.
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 when examining the disease 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 mesothelioma genes and proteins.
Measuring a person’s gene and protein expression may lead to an individualized treatment regimen that is effective in controlling each patient’s unique cancer. Gene analysis can also help doctors provide a more precise prognosis for patients.
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One of the best ways to improve your prognosis and the likelihood of beating mesothelioma is through clinical trials.
Clinical trials can provide:
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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 proteins that aid tumors. 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 irrelevant in stopping the growth of 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. In one recent study, 70 out of 74 participants (95%) suffered 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 that mesothelioma cells are harmless. A lot of immunotherapy drugs focus on PD-L1, particularly how to stop the bridge it 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 United States Food and Drug Administration recently approved Keytruda (the brand name for the immunotherapy drug pembrolizumab) for mesothelioma cases with high PD-L1 levels.
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 a mesothelial cell that has become cancerous.
In the aforementioned study, published 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 the presence of mesothelioma.
Researchers are investigating ipilimumab, which is a checkpoint inhibitor immunotherapy drug. The therapy, which has the brand name Yervoy, blocks the attachment of B7 and CTLA-4.
The Emergence of Gene Therapy for Mesothelioma
Mesothelioma gene therapy has become one of the leading innovative treatments for mesothelioma. There are three types: blocking cancerous genes and proteins; adding cancer-fighting genes to the body; or fixing damaged and mutant mesothelioma genes.
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, meaning the treatment at least stalled the growth of their cancer.
TR002 is an example of adding a gene to the body. 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. A disease-control rate of 87.5% highlighted a recent study investigating TR002.
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 and involve cross-checking 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 that create 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 and stifle the cancer.
“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 ineffective 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.
Show 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.