Mesothelioma is a rare cancer primarily caused by asbestos exposure, but genetics can also influence its development. The BAP1 gene, or BRCA1-associated protein 1, is a major factor in this genetic link. Mutations in this gene affect a person’s risk, prognosis, and treatment options for mesothelioma.
The BAP1 Gene and Its Function
The BAP1 gene provides instructions for a protein that acts as a tumor suppressor, which helps prevent uncontrolled cell growth. Functioning correctly, the BAP1 protein operates within the cell’s nucleus to regulate cell division and ensure it occurs in an orderly manner.
A primary role of the BAP1 protein is to help repair damaged DNA. It is part of the cellular machinery that identifies and mends breaks in DNA strands. This process maintains the integrity of the genome and is a defense against changes that can lead to cancer.
The BAP1 protein accomplishes its tasks through a process called deubiquitination. It removes small molecules called ubiquitin from other proteins, which alters their function and interactions within the cell. By controlling the ubiquitin status of proteins involved in the cell cycle and DNA damage response, BAP1 helps orchestrate these cellular activities.
The Link Between BAP1 Mutations and Mesothelioma Development
A mutation in the BAP1 gene disables its tumor-suppressing function, in what is often called a “loss-of-function” mutation. Without a working BAP1 protein, a cell’s ability to repair DNA damage is impaired. This leaves the cell vulnerable to accumulating genetic errors that can lead to uncontrolled growth and tumor formation.
The link to asbestos exposure is clear in mesothelioma. Asbestos fibers cause chronic inflammation and damage to mesothelial cells, the cells that line the chest and abdomen. While a healthy BAP1 gene helps repair this damage, a mutated gene leaves cells less capable of mending asbestos-induced DNA breaks, increasing their susceptibility to becoming cancerous.
This inherited susceptibility is known as BAP1 Tumor Predisposition Syndrome (BAP1-TPDS). Individuals with this syndrome inherit one mutated copy of the BAP1 gene from a parent and have a higher lifetime risk for certain cancers. Mesothelioma is a hallmark cancer of BAP1-TPDS, especially for those exposed to asbestos. Studies in mouse models confirm that a Bap1 mutation leads to a higher rate and faster development of asbestos-induced mesothelioma.
Prognosis and Treatment Implications
For individuals with mesothelioma, a germline BAP1 mutation has a counterintuitive link to prognosis. Studies show that patients with inherited BAP1 mutations often experience longer survival times compared to those with sporadic mesothelioma, which is not linked to an inherited mutation. The median survival for these patients can be several years, a stark contrast to the typical survival of less than a year for sporadic cases.
This improved prognosis may be because tumors with BAP1 mutations are less aggressive and more responsive to certain treatments. The same DNA repair deficiency that contributes to cancer can also be a vulnerability. Cancer cells with a compromised ability to fix DNA damage are more susceptible to treatments that cause further DNA breaks, like certain chemotherapies.
This has led to targeted therapies, particularly PARP inhibitors. These drugs block an alternative DNA repair pathway, which can lead to cell death in cancer cells that already have a faulty system due to a BAP1 mutation. While clinical trials have shown mixed results, research is ongoing to determine the effectiveness of PARP inhibitors like olaparib. Interest also exists in how BAP1 status affects immunotherapy responsiveness, but data remains inconclusive.
Hereditary Risk and Genetic Testing
BAP1 Tumor Predisposition Syndrome is inherited in an autosomal dominant manner. This means a child of a person with the mutation has a 50% chance of inheriting it, creating a hereditary risk for close relatives.
Genetic counseling and testing are recommended for individuals with a personal or strong family history of associated cancers. Indicators for testing include multiple of these cancers in a family, a diagnosis at a young age, or the presence of benign skin lesions known as BAP1-inactivated melanocytic tumors. Cancers associated with the syndrome include:
- Mesothelioma
- Uveal (eye) melanoma
- Cutaneous (skin) melanoma
- Renal cell carcinoma (kidney cancer)
Genetic testing involves analyzing a blood or saliva sample for pathogenic variants in the BAP1 gene. Identifying a mutation allows family members to understand their cancer risks and take proactive steps. These steps may include enhanced surveillance, like regular skin and eye exams, and avoiding carcinogens like asbestos and excessive UV exposure.