Bap1 Tumor Predisposition Syndrome

BAP1 tumor predisposition syndrome, or: BAP1-TPDS, is associated with an increased risk of "BAP1-inactivated melanocytic tumor" (BIMT; formerly called atypical Spitz tumor), and the following tumor types (in descending order of frequency):

• uveal melanoma (UM)
• malignant mesothelioma (MMe)
• melanoma (of the skin) (CM)
• renal cell carcinoma (RCC)
• basal cell carcinoma (BCC)

Furthermore, the following malignancies may also be associated with BAP1-TPDS:

• Hepatocellular carcinoma
• Cholangiocarcinoma
• meningioma.

Other suspected but unconfirmed tumors in BAP1-TPDS include (in alphabetical order): Breast cancer, urinary bladder cancer, neuroendocrine carcinoma, non-small cell lung adenocarcinoma, thyroid cancer. Affected individuals may have more than one primarius at a time.

BAP1 tumor predisposition syndrome is caused by pathogenic variants in the BAP1 gene . It is inherited in an autosomal dominant manner. BAP1 is a deubiquitylase. It binds to BRCA1 (breast cancer type 1 susceptibility protein) through its RING finger domain and acts as a tumor suppressor. In addition, the enzyme may be involved in the regulation of transcription, cell cycle and growth, DNA damage response and chromatin dynamics.

So far, only point mutations in BAP1 have been described, but the occurrence of deletions or duplications of larger gene segments cannot be excluded.

In general, the median age of onset of these tumors is younger than in the general population.

Criteria for clinical diagnosis have not yet been established, but suspicion exists in patients who meet any of the following:

• at least two confirmed BAP1-associated tumors
• or
• One BAP1-associated tumor and a first- or second-degree relative with a confirmed BAP1-associated tumor (not basal cell carcinoma and/or cutaneous melanoma due to the high frequency in the population).

Consensus recommendations on screening for carriers have not yet been established. However, it is recommended to perform annual check-ups of the eyes and skin with regard to uveal melanomas and skin lesions, respectively. Regarding renal cell carcinoma, screening according to von Hippel-Lindau syndrome can be performed.

The tumor suppressor gene BAP1 encodes a deubiquitinase enzyme that is involved in various cellular activities, including DNA repair and apoptosis. The nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline variants predispose to cancer with loss of function. Remarkably, there are very rare examples of different germline variants of the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome (Küry S et al. 2022).

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