Asbestos exposure is well established as the primary risk factor and cause of mesothelioma cancer, but other risk factors have been presented in recent decades. Such factors include a virus called Simian Virus 40, erionite exposure and genetic predispositions. The latter has recently sparked debate as researchers from Hawaii have discovered a gene that may be able to identify those with a higher risk for developing this type of asbestos-related cancer.
One of the biggest questions facing mesothelioma researchers is why some people exposed to asbestos and erionite develop the cancer and others do not. While exposure levels and the duration of exposure play significant roles, researchers have found that some people are just more susceptible to asbestos and erionite fibers. For example, 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 cancer.
In Cappadocia, Turkey, certain families in specific villages are more likely to develop the cancer after exposure to erionite, a naturally occurring mineral that shares a similar structure to asbestos. Doctors believe these families are genetically predisposed to developing it. Genetic factors were first acknowledged in a study among family members who had contracted the cancer and were missing a specific gene.
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Researchers were first inclined to study genetics as a risk factor for mesothelioma after the cancer was found more commonly among family members in the 1960s. Since, many studies have been conducted and researchers have identified some genes that may play a role in its development.
For example, in one study of a family of three sisters with the malignant form of the cancer and one brother with pleural plaques — who were all exposed to asbestos by living near an asbestos cement factory — the siblings lacked a chromosomal structure at the 9p gene region. This gene — known as a tumor suppressor — is related to cancer suppression when present, and the lack of it enables tumor growth and the development of mesothelioma. Other tumor suppressor genes that may affect development include P16INK4a, P16/CDKN2A, P14ARF and neurofibromatosis 2 (NF2).
Two other genes that have been commonly associated with this asbestos cancer include glutathione-S-transferase M1 (GSTM1) and N-acetyltransferase (NAT2). GSTM1 is important in the detoxification of carcinogens such as asbestos, and NAT2 is involved in the biotransformation of carcinogens. The absence of GSTM1 can result in a twofold increase in risk for mesothelioma and the absence of both GSTM1 and NAT2 increases a person's risk sevenfold.
Recent research unveiled a gene that may play a significant role in a person's likelihood of developing mesothelioma. In a 2011 study conducted by researchers at the University of Hawaii Cancer Center and Fox Chase Cancer Center in Philadelphia, Pennsylvania, it was discovered that people who carry a mutation in a gene called BAP1 are susceptible to developing the cancer. The gene is located on the short arm of chromosome three. It is more commonly known as BRAC1, a gene known for its association with breast cancer. When these individuals are exposed to asbestos or a similar mineral like erionite, their risk for contracting it is significantly increased.
The study evaluated two U.S. families with high incidences of mesothelioma and the mutation of the BAP1 gene. Researchers noticed that every family member who had contracted the disease also carried the BAP1 mutation.
Further investigation into 26 individuals with the illness, but without a family history of the cancer, confirmed the connection, with 25 percent of those studied carrying mutations of the BAP1 gene.
Testing for inherited gene mutations is a potentially valuable, minimally invasive screening tool for doctors who treat asbestos-related diseases. If a mutation is not found in someone with asbestosis, for example, it can temper a high-risk individual's fear of increased susceptibility for mesothelioma and other cancers. And if doctors do in fact locate a BAP1 mutation, they can provide a patient with steps to minimize the risk of developing mesothelioma and other cancers, such as avoiding workplace exposures to asbestos and other toxins.
In addition, finding a BAP1 mutation before cancer has the chance to develop allows doctors to initiate a screening process and create a schedule for routine exams. In the future, early detection of this mutation could identify patients who would benefit from novel therapeutic interventions currently being tested in clinical trials, such as the use of gene therapy to restore the gene's tumor suppressing function.
Testing for BAP1 requires a blood sample. It takes around three to four weeks to get results. A positive result means the gene is mutated and a negative result means the gene is normal. The test may not be covered by insurance and costs around $1,000 to perform.
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"As I say to patients, when hope is part of the equation, anything is possible," he said. "I remain optimistic that we can, in the next decade, put together the right combination of patients and treatment to effect a cure, which is our holy grail."
Research indicates that a mutation in the BAP1 gene may increase a person's susceptibility to various cancers.
These cancers include:
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Many patients with this mutation develop a specific type of skin tumor known as MBAITs — an acronym for melanocytic BAP1-mutated atypical intradermal tumors. These noncancerous growths can serve as a visual marker for patients with this mutation and an indication of risk for developing mesothelioma or other cancers.
MBAITs are pink and tan in color and range from 0.2 to 1.0 cm in diameter. The benign growths resemble moles or beauty marks. They are often flat or slightly elevated. Because of their unique shape, doctors can distinguish MBAITs from other skin tumors such as Spitz nevus and AST lesions.
Three villages in Turkey provide an example of how genetic factors can play a role in mesothelioma development. In the villages of Tuzkoy, Karain and "Old" Sarihidir, where approximately 50 percent of all deaths are caused by malignant mesothelioma, some families have higher incidences of the cancer even though erionite exposure levels are the same for other families in the area. The initial suggestion from researchers studying this occurrence was that a unique and more carcinogenic form of erionite was present in certain houses, but an evaluation of the structure of erionite from different homes proved the fiber structures were similar.
Additional studies showed that when family members at high-risk of developing the cancer married into families with no history of the disease, their children developed the cancer. This finding — along with subsequent studies that found more evidence of genetic predisposition — has convinced many researchers that inherited genetics is responsible for higher susceptibility to erionite exposure and mesothelioma in the region. Although the relationship between genetic susceptibility and an asbestos-related cancer is still being investigated, the situation in Turkey presents a strong argument for genetics playing a role in the disease.
Research is beginning to show the value of genetic testing to improve prognostic predictions. Currently, it is difficult for doctors to predict which patients will live longer than the average. In the future, genetic testing may provide more accurate estimations of how long someone may live with mesothelioma.
A 2014 study led by Dr. Michele Carbone of the University of Hawaii Cancer Center found mesothelioma patients with the BAP1 mutation lived at least four years longer than patients without the mutation. The five-year survival rate was 47 percent for those with the mutation, compared to the typical survival rate of just 6.7 percent.
It seems BAP1 increases the risk of developing mesothelioma, but it also improves chances of long-term survival. In the future, this could mean that people with the BAP1 gene could receive more aggressive treatment because research shows they respond better than the average patient.
In 2015, a study on peritoneal mesothelioma found two genes that contributed to shorter survival. The genes, CDKN2A and NF2, seem to make peritoneal mesothelioma more aggressive and less responsive to surgery with heated chemotherapy.
More research is necessary, but in the future, this finding may help identify which patients may not benefit from aggressive cancer treatment, helping people to make more informed decisions about treatment.
Identifying gene mutations may be able to help doctors with detecting mesothelioma in its early stages. In a 2012 study published in the Journal of Translational Medicine, researchers diagnosed four early-stage mesothelioma patients based on suspicion of a BAP1 mutation. This early diagnosis improved prognosis, as the patients experienced survivals of five to 10 years.
As ongoing studies 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.
Dr. Yang of the University of Hawaii Cancer Center is one of many doctors who celebrated this progressive moment in mesothelioma's history. "We are very excited about this discovery," Yang said. "The next step is to translate this discovery into actual treatments for mesothelioma patients."
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