From the blog

BAP1 and Mesothelioma Risk

Published: March 17, 2023

Researchers have found at least one way that asbestos causes mesothelioma. The disease is linked to the HMGB1 protein. Researchers looked at a mesothelioma epidemic in Türkiye, noting that in some families, up to 50 percent develop mesothelioma. Family members passed the likelihood of mesothelioma from generation to generation.  Families in the United States have also noticed that they were more susceptible to the cancer. When researchers studied the families, their mesothelioma was caused by inherited germline mutations in BAP1, which was passed on from family member to family member. There is a 50 percent chance of inheriting the mutation, and the people who inherit it develop mesothelioma. These studies of germline mutations are important because people whose mutations are identified have a median survival of six to seven years from the time of diagnosis because of treatment. There are even some who live anywhere from 10 to 20 years and die from something else.

Once asbestos is inhaled, it becomes lodged in the pleura or peritoneum, and the HMGB1 protein is released. Inflammatory cells respond to the released protein, causing chronic inflammation. The inflammation lasts for a long time, becoming a chronic issue since the body cannot easily remove asbestos fibers. The asbestos causes DNA changes, with more asbestos in the body causing more DNA mutations. Over time, this could be the cause for mesothelioma. In can take anywhere from 20 to 60 years to develop the cancer. In lab studies, mice given aspirin daily reduced inflammation caused by HMGB1, leading to less mesothelioma cases. All cells of the body have germline mutations, but BAP1 germline mutations lead to cancer. Almost 100 percent of the cases of BAP1 genetic mutations lead to cancer, often times multiple cancers during a person’s lifetime. Around 30 percent of BAP1 mutations lead to mesothelioma. Other common cancers stemming from BAP1 mutations include eye and skin melanomas, renal cell carcinomas, and breast cancer. BAP1 is the most common germline mutation that causes mesothelioma. Laboratories in the United States have found that around 12 percent of mesothelioma cases develop in people that have BAP1 or other gene germline mutations.

There are now multiple clinical trials for those with germline BAP1 mutations in Bethesda, Maryland. People carrying the germline mutation are eligible, even if they don’t have cancer. People with the mutation can receive free screening, which can be lifesaving since the BAP1 gene increased the risk of multiple types of cancer. If patients need therapy, it is also given at no cost. Lodging and travel are also covered by the federal government.

BAP1 is an important gene for mesothelioma research. Around 60 to 70 percent of all mesotheliomas studied had BAP1-inactivating mutations, meaning it is the most mutated gene in mesothelioma. Understanding the gene could possibly help researchers prevent mesothelioma in the future. The mutations are acquired, which means they happen when mesothelial cells turn into cancerous mesothelioma cells, but some mutations are present since birth. Patients with BAP1 related mesothelioma cases typically have improved survival but when the mutations are only in tumor cells, survival is not as good as patients who have BAP1 mutation in the germline. If we figure out how patients with acquired BAP1 mutations live longer with mesothelioma, we could apply this knowledge and help all patients with mesothelioma.

Jiaming Xue et al., “Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy” PNAS (September 30, 2020). [Link]
Michele Carbone et al., “Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer” Cancer Discovery (August 2020). [Link]
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