BAP1 Gene Mutation

BAP1 is a tumor suppressor gene that doctors use as a biomarker to aid in the detection of various cancers. A 2011 study funded by the National Cancer Institute (NCI) discovered that a mutation in the BAP1 gene significantly increases a person’s risk for developing mesothelioma following an exposure to asbestos.
After observing numerous cases where malignant mesothelioma was diagnosed in multiple members of a single family, researchers began to investigate hereditary predispositions for the disease. Within these families, some studies found evidence of BAP1 mutations in every family member diagnosed with mesothelioma. This finding suggests that as a direct result of a BAP1 mutation, a strong family history of mesothelioma may increase a person’s susceptibility for the disease and the overall risk of developing it.
Testing for inherited gene mutations such as a defective BAP1 gene can be a valuable, minimally-invasive screening tool for mesothelioma oncologists. If a mutation is not found, for example, it can alleviate 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 immediately provide a patient with steps to minimize the risk of developing mesothelioma, such as avoiding workplace exposures to asbestos.
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 a BAP1 mutation could identify patients who would benefit from novel therapeutic interventions currently being tested in mesothelioma clinical trials, such as the use of gene therapy to restore the gene’s tumor suppressing function.

Genetics, the BAP1 Gene and Their Links to Cancer

As researchers discover more about the cellular processes that trigger the onset of mesothelioma and other cancers, they continue to unveil the increasingly important role that genetics plays as a risk factor for these diseases. Genetics is a branch of science that explores the structure and function of our genes, the sections of our DNA that tell our cells how and when to perform crucial activities that keep our bodies healthily functioning.
Changes in our genetic material commonly occur when our cells make copies of themselves, and environmental factors such as exposure to the sun and airborne asbestos can also damage our DNA. Because our cells have mechanisms to repair such damage, the majority of the genetic errors we accumulate are not passed on to our children.
But DNA damage to some types of cells can be passed along to the next generation, which can cause hereditary diseases ranging from colorblindness and diabetes to Down syndrome and cancer. When damaged DNA has adverse consequences, this is known as a genetic mutation. And while some genetic changes are harmless, certain mutations can inhibit the proper functioning of important genes, allowing uncontrolled cancer cells to grow and spread.
We have determined that mutations in the BAP1 gene disable it from performing its role as a tumor suppressor and preventer of metastasis. Researchers have identified more than 30 tumor suppressor genes that are responsible for stopping cell division, repairing damaged DNA and killing cells that cannot be repaired. When tumor suppressor genes like BAP1 mutate, these mechanisms are inactivated and a person becomes genetically predisposed to cancer.

Cancers Associated with a BAP1 Mutation

Research indicates that a mutation in the BAP1 gene may increase a person’s susceptibility to various cancers, including:

• Mesothelioma
• Breast cancer
• Pancreatic cancer
• Ovarian cancer
• Kidney cancer
• Skin cancer
• Uveal melanoma

Researchers have found that a high percentage of people carrying a BAP1 gene mutation are more prone to developing various benign and malignant tumors, including skin cancer, malignant mesothelioma and uveal melanoma (a rare cancer of the eye).
In one study conducted at the University of Hawaii, BAP1 gene mutations were associated with breast cancer, ovarian cancer, pancreatic cancer, renal cancer and mesothelioma. This finding prompted a follow-up study, in which researchers examined 26 patients diagnosed with mesothelioma.
Of this group, 25 percent carried BAP1 mutations. Two patients had germline mutations — a BAP1 defect they inherited from their parents. These individuals were also diagnosed with melanoma of the eye, which indicated a genetic predisposition to cancer. Donald Blair, a doctor at the National Cancer Institute, commented that “this provides yet another example of the critical importance of the detailed genetic analysis of human tumors."

Visible Signs of a BAP1 Mutation

Many patients with BAP1 mutations develop a specific type of skin tumor known as MBAITs. Short for melanocytic BAP1-mutated atypical intradermal tumors, these noncancerous growths can serve as a visual marker for patients with a BAP1 mutation and, consequently, a heightened risk of developing mesothelioma.
MBAITs are pink and tan in color and range from 0.2 to 1.0 cm in diameter. Mole-like in appearance, the tumors 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.
A 2012 study by Dr. Michele Carbone and colleagues focused on two families with BAP1 mutations. Results indicated that in one family, four out of five members carried a germline BAP1 mutation and had one or more MBAITs. In the second family, all seven members had the BAP1 mutation and four had MBAITs.
In a second study conducted by the same researchers, 118 individuals were divided into two groups based on the presence or absence of the BAP1 gene mutation. A significantly higher incidence of malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs was observed in the group with the BAP1 mutation.

BAP1 Mutation Studies

In addition to Carbone's findings, other researchers have identified noteworthy trends in individuals with BAP1 mutations. A study by Bott et al. located BAP1 mutations in 23 percent of the 53 pleural mesothelioma patients studied. Half of the patients reported a past exposure to asbestos. In another group of mesothelioma patients without a history of asbestos exposure, Bott identified BAP1 mutations in 18 percent of the 68 patients studied.
In 2010, Harbour et al. completed a study indicating that the loss of BAP1 encouraged the spread of uveal melanoma. With a loss of BAP1 found in 84 percent of metastasizing tumors, these findings suggest that the BAP1 pathway may be a prime target for intervention with gene therapy.
Information gleaned from these and other studies affirms a definitive link between BAP1 mutation, mesothelioma, uveal melanoma, MBAITs and several other cancers. The studies also stress the need to further examine why these mechanisms are connected and whether or not BAP1 mutations can be prevented.

The Future of BAP1 Research

Researchers are hopeful that research on the BAP1 gene will lead to new targeted therapies for mesothelioma patients.

Identifying BAP1 gene mutations can 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 ten 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 BAP1 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,” said Yang. “The next step is to translate this discovery into actual treatments for mesothelioma patients."