BAP1 Tumor Predisposition Syndrome

Clinical characteristics: BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk for a specific skin lesion, BAP1-inactivated melanocytic tumors (BIMT; formerly called atypical Spitz tumors), and the following cancers, in descending order of frequency: uveal (eye) melanoma (UM), malignant mesothelioma (MMe), cutaneous melanoma (CM), renal cell carcinoma (RCC), and basal cell carcinoma (BCC). Hepatocellular carcinoma, cholangiocarcinoma, and meningioma may also be associated with BAP1-TPDS. Affected individuals can have more than one type of primary cancer. In general, the median age of onset of these tumors is younger than in the general population. UM tends to be a more aggressive class 2 tumor with higher risk for metastasis and reduced survival compared to UM occurring in the general population. Due to the limited number of families reported to date, the penetrance, natural history, and frequencies of BAP1-associated tumors are yet to be determined. Other suspected but unconfirmed tumors in BAP1-TPDS include (in alphabetic order): breast cancer, neuroendocrine carcinoma, non-small-cell lung adenocarcinoma, thyroid cancer, and urinary bladder cancer.

Diagnosis/testing: The diagnosis of BAP1-TPDS is established in a proband by identification of a heterozygous germline pathogenic variant in BAP1 on molecular genetic testing.

Management: Treatment of manifestations: Treatment of CM and BCC per established clinical guidelines. UM: because of the increased aggressiveness of BAP1-related UM, management should be the same as the more aggressive class 2 or monosomy 3 tumors. MMe treatment per oncologist familiar with BAP1-MMe; RCC treatment per established management guidelines.

Prevention of primary manifestations: UM: avoid arc-welding. MMe: avoid asbestos exposure (including naturally occurring tremolite and erionite) and smoking. CM and BCC: limit sun exposure, use sunscreen and protective clothing, and have regular dermatologic examinations.

Surveillance: BIMT, CM, BCC: annual full-body dermatologic examinations beginning around age 18 years. Baseline whole-body imaging in those with a large number of lesions; repeat as needed. Biopsy of BIMT is not recommended unless lesions grow or change in shape or color. UM: yearly dilated eye examinations and at least baseline fundus imaging beginning around age 11 years. Refer any pigmented intraocular lesion to an ocular oncologist for follow up and management. MMe: no screening modalities exist; however, annual physical examination is recommended. If an abdominal MRI is to be performed as recommended for RCC, consider evaluation of the peritoneum and pleura as well. While some physicians recommend spiral chest CT for asymptomatic persons with a history of exposure to asbestos, others do not, given the possible increased risk of cancer from radiation exposure. RCC: annual clinical examination; abdominal ultrasound every two years alternating with MRI every two years starting at age 30 years.

Agents/circumstances to avoid: Arc welding, asbestos including naturally occurring tremolite and erionite, smoking, unnecessary and prolonged sun exposure, routine chest x-ray and CT examinations.

Evaluation of relatives at risk: Clarify the genetic status of at-risk relatives by molecular genetic testing for the BAP1 pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of screening and preventive measures.

Genetic counseling: BAP1-TPDS is inherited in an autosomal dominant manner. To date, most individuals diagnosed with BAP1-TPDS have an affected parent; the proportion of BAP1-TPDS caused by a de novo pathogenic variant is unknown. Each child of an individual with BAP1-TPDS has a 50% chance of inheriting the BAP1 pathogenic variant; however, penetrance appears to be incomplete and the types of BAP1-related tumors can vary among different members of the same family. Once the germline BAP1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.