BAP1 tumor predisposition syndrome is an inherited disorder that increases the risk of a variety of cancerous (malignant) and noncancerous (benign) tumors, most commonly certain types of tumors that occur in the skin, eyes, kidneys, and the tissue that lines the chest, abdomen, and the outer surface of the internal organs (the mesothelium). Affected individuals can develop one or more types of tumor, and affected members of the same family can have different types.

Some people with BAP1 tumor predisposition syndrome develop growths in the skin known as atypical Spitz tumors. People with this syndrome may have more than one of these tumors, and they can have dozens. Atypical Spitz tumors are generally considered benign, although it is unclear if they can become cancerous. Skin cancers are also associated with BAP1 tumor predisposition syndrome, including cutaneous melanoma and basal cell carcinoma.

A type of eye cancer called uveal melanoma is the most common cancerous tumor in BAP1 tumor predisposition syndrome. Although uveal melanoma does not usually cause any symptoms, some people with this type of cancer have blurred vision; small, moving dots (floaters) or flashes of light in their vision; headaches; or a visible dark spot on the eye.

People with BAP1 tumor predisposition syndrome are at risk of developing malignant mesothelioma, which is cancer of the mesothelium. When associated with BAP1 tumor predisposition syndrome, malignant mesothelioma most often occurs in the membrane that lines the abdomen and covers the abdominal organs (the peritoneum). It less commonly occurs in the outer covering of the lungs (the pleura).

A form of kidney cancer called clear cell renal cell carcinoma is also associated with the condition. Researchers are still determining whether other forms of cancer are linked to BAP1 tumor predisposition syndrome.

When they occur in people with BAP1 tumor predisposition syndrome, cancers tend to arise at a younger age and are often more aggressive than cancers in the general population. The cancerous tumors in BAP1 tumor predisposition syndrome tend to spread (metastasize) to other parts of the body. Survival of affected individuals with this syndrome is usually shorter than in other people who have one of these cancers. However, individuals with malignant mesothelioma as part of the BAP1 tumor predisposition syndrome appear to survive longer than those who have the cancer without the syndrome.

BAP1 tumor predisposition syndrome is caused by mutations in the BAP1 gene. The BAP1 protein acts as a tumor suppressor, which means it helps prevent cells from growing and dividing too rapidly or in an uncontrolled way. Its function is to remove molecules called ubiquitin from certain proteins (deubiquitination), which can affect the activity of the protein and its interactions with other proteins. By removing ubiquitin, BAP1 helps regulate diverse cellular processes. The BAP1 protein is thought to be involved in cell growth and division (proliferation), cell death, repair of damaged DNA, and control of gene activity.

Mutations in the BAP1 gene lead to production of an altered protein that cannot function normally and may be broken down prematurely. In addition to an inherited (germline) mutation in one copy of the gene, which is found in essentially every cell of the body, a second, non-inherited (somatic) mutation usually occurs in the normal copy of the gene in cells that give rise to tumors. Together, the germline and somatic mutations result in a complete loss of BAP1 protein function in tumor cells. A shortage of this protein's function likely impairs the removal of ubiquitin from certain proteins. Although it is unclear exactly how loss of BAP1 function leads to BAP1 tumor predisposition syndrome, researchers speculate that altered activity of proteins normally regulated by BAP1 deubiquitination may promote cell proliferation or survival, resulting in tumor formation.

Studies suggest that environmental and lifestyle factors help determine which types of tumor develop in individuals with BAP1 tumor predisposition syndrome. For example, exposure to asbestos likely contributes to the development of malignant mesothelioma. While asbestos increases the risk of malignant mesothelioma in the general population, the risk is even higher in individuals with a BAP1 gene mutation. It is not clear why certain tumor types are particularly associated with BAP1 tumor predisposition syndrome.

Normal Function

The BAP1 gene provides instructions for making a protein called ubiquitin carboxyl-terminal hydrolase BAP1 (shortened to BAP1). This protein functions as a deubiquitinase, which means it removes a molecule called ubiquitin from certain proteins. The presence of ubiquitin molecules on a protein can affect the activity of the protein and its interactions with other proteins. The ubiquitin "tag" also promotes breakdown (degradation) of a protein. By removing ubiquitin, BAP1 helps regulate the function of many proteins involved in diverse cellular processes. The BAP1 protein is thought to help control cell growth and division (proliferation) and cell death. Studies suggest that it is involved in the progression of cells through the step-by-step process they take to replicate themselves (called the cell cycle) and that it plays roles in repairing damaged DNA and controlling the activity of genes.

Although the exact mechanism is unclear, the BAP1 protein acts as a tumor suppressor. Tumor suppressor proteins help prevent cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

BAP1 tumor predisposition syndrome

Mutations in the BAP1 gene cause BAP1 tumor predisposition syndrome. People with this condition have an increased risk of developing many types of noncancerous (benign) and cancerous (malignant) tumors, particularly certain tumors of the skin (atypical Spitz tumors, cutaneous melanoma, and basal cell carcinoma); eyes (uveal melanoma); kidneys (clear cell renal cell carcinoma); and a tissue called the mesothelium that lines the chest, abdomen, and internal organs (malignant mesothelioma). Researchers are still determining whether other forms of cancer are linked to BAP1 tumor predisposition syndrome.

Affected individuals inherit a mutation in one copy of the BAP1 gene. These mutations, which are present in essentially every cell of the body, are classified as germline mutations. Most germline BAP1 gene mutations lead to an abnormally short BAP1 protein that is likely broken down prematurely. Other germline mutations change single protein building blocks (amino acids) in the BAP1 protein and likely impair its function. In most cases, a second, non-inherited (somatic) mutation occurs in the normal copy of the gene in cells that give rise to tumors. Together, the germline and somatic mutations lead to a loss of BAP1 protein function in tumor cells.

Reduction or loss of this protein's function likely prevents the removal of ubiquitin molecules from certain proteins. Although it is unclear exactly how changes in BAP1 function lead to BAP1 tumor predisposition syndrome, researchers speculate that altered activity of proteins normally regulated by BAP1 deubiquitination may promote cell proliferation or survival, resulting in tumor formation.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Melanoma

MedlinePlus Genetics provides information about Melanoma

Other cancers

Somatic BAP1 gene mutations have been found in uveal melanoma, malignant mesothelioma, and clear cell renal cell carcinoma tumors in the absence of a germline BAP1 gene mutation. In these cases, the cancers occur in people with no family history of the cancer and are considered sporadic. Affected individuals do not develop additional tumor types associated with BAP1 tumor predisposition syndrome (described above).

Other Names for This Gene

• BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)
• cerebral protein 6
• cerebral protein-13
• HUCEP-13
• hucep-6
• KIAA0272
• ubiquitin carboxyl-terminal hydrolase BAP1
• UCHL2

Genomic Location

BAP1 tumor predisposition syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered BAP1 gene increases the chance of developing one or more tumors. In most cases, an affected person has one parent with the condition.

People with a mutation in the BAP1 gene inherit an increased risk of tumor formation. Not all people with a gene mutation will develop a tumor.

BAP1 tumor predisposition syndrome is a rare condition; its prevalence is unknown. More than 70 families with the condition have been described in the medical literature.