Genetic Disorder Reference Sheet: BAP1
Isolated in 1998 as a tumor suppressor gene, BAP1 pathogenic variants have been identified (https://doi.org/10.1158/2159-8290.cd-19-1220) in at least 200 families. More cases will be found as germline pathogenic variant testing becomes more readily available and routinely offered to patients with cancer.
Cancer Risk
BAP1 pathogenic variants are associated with increased risk (https://www.ncbi.nlm.nih.gov/books/NBK390611/) for malignancies and tumors. BAP1 tumor predisposition (BAP1-TPDS) characteristics (https://doi.org/10.1158/2159-8290.cd-19-1220) include:
- BAP1-inactivated melanocytic tumors (formerly called atypical Spitz tumor) are flesh colored to reddish brown and average 5 mm in diameter. Both copies of BAP1 are inactivated, leading to loss of staining for the BAP1 protein on immunohistochemistry. The tumors usually have the somatic BRAF pathogenic variant p.Val600Glu.
- Uveal melanoma tumors are generally more aggressive with a higher risk for metastasis and reduced survival; median age at onset is 53 years compared to 62 years in general population.
- Median age of onset for mesothelioma is 55–58 years with BAP1 variants compared to 62–68 years in the general population. Diagnoses are 80% pleural mesothelioma and 20% peritoneal mesothelioma.
- Cutaneous melanoma is the third most common cancer in people with a BAP1 pathogenic variant with a median age of 39 years compared to 58 years in the general population.
- Renal cell cancer has a median age of 47 years compared to 64 years in the general population.
Other cancers that may be associated with BAP1 pathogenic variants include multiple basal cell skin cancers, breast cancer, cholangiocarcinoma, meningioma, neuroendocrine tumors, non-small cell lung adenocarcinoma, and thyroid cancer, but the risk is not understood.
Biomarker Testing
Germline biomarker testing should be offered to any individual with two or more BAP1-TPDS characteristics or individuals with a BAP1-TPDS characteristic and a relative with one BAP1-TPDS characteristic (excluding two basal cell cancers or cutaneous melanomas because of their high frequency in the general population). First- and second-degree relatives of people with known BAP1 pathogenic variants should also be offered testing.
Prevention and Early Detection
Intensive surveillance (https://doi.org/10.1016/j.ejca.2017.12.022) can lead to early detection (https://www.ncbi.nlm.nih.gov/books/NBK390611/) when treatment is most likely to be effective. People with BAP1 pathogenic variants should obtain annual:
- Dilated eye examinations and imaging (i.e., direct and indirect ophthalmoscopy, fundus photography, and ocular ultrasound) from an ocular oncologist beginning at approximately age 11
- Full body dermatologic examinations beginning at approximately age 12
- Abdominal magnetic resonance imaging (consider also evaluating the peritoneum and pleura) alternating with ultrasound for clear cell renal carcinoma beginning around age 30
Educate patients about lifestyle prevention measures, including:
- Avoiding arc welding because of risk of uveal melanoma
- Consistently using sunglasses with high UVA and UVB protection
- Avoiding asbestos exposure and tobacco use
- Limiting sun exposure, using sunscreen with an SPF of 30 or higher, and wearing protective clothing, including hats
Mesothelioma has no reliable early disease symptoms or screening modalities, but people with BAP1 pathogenic variants should obtain annual physical examinations for late manifestations, including chest pain, cough, fever, shortness of breath, dysphagia, hoarseness, weight loss, fever, upper body and face edema, abdominal pain, ascites, nausea, vomiting, and constipation.
Implications for Nurses
Because screening measures are recommended for children, families with known pathogenic BAP1 variants should consider testing at age 10. Credentialed genetics professionals can assist families with that process.
BAP1 is a susceptibility biomarker (https://doi.org/10.1158/2159-8290.cd-19-1220) that indicates a person’s potential for developing multiple malignancies. Identifying the pathogenic variant in those individuals allows them to consider more intensive surveillance and prevention measures and potentially reduce morbidity and mortality.
It also serves as a prognostic biomarker (https://doi.org/10.1158/2159-8290.cd-19-1220): People with a germline BAP1 pathogenic variant tend to live longer with mesothelioma, suggesting it is a less aggressive form, whereas those with uveal melanoma may have a poorer prognosis.
However, its value as a predictive biomarker (https://doi.org/10.1158/2159-8290.cd-19-1220) is limited at this time: Mesothelioma, metastatic uveal melanoma, metastatic renal cell carcinoma, and other BAP1-related malignancies are resistant to current therapies and are an active area of research (https://doi.org/10.1093/jnci/djy171).