BAP1 tumor predisposition syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

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.

Which doctor should you see?

The suggested department for discussing BAP1 tumor predisposition syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for BAP1 tumor predisposition syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.