BAP1 Tumour Predisposition Syndrome

What BAP1 Does

BAP1 is the catalytic subunit of the PR-DUB complex, which removes the mono-ubiquitin mark from histone H2A at lysine 119, a mark placed by polycomb complex 1. Through this and other substrates BAP1 influences transcription, DNA repair and cellular metabolism.

It was first identified through its interaction with BRCA1, though its principal tumour-suppressor activity is now understood to be chromatin-associated rather than a direct role in homologous recombination.

The Predisposition Syndrome

Germline pathogenic BAP1 variants predispose to malignant mesothelioma, uveal (eye) melanoma, clear cell renal cell carcinoma, cutaneous melanoma, and characteristic benign melanocytic skin tumours sometimes called BAP1-inactivated melanocytic tumours.

Penetrance and the exact tumour spectrum are still being refined, and management follows specialist genetics guidance. Separately, rare germline missense variants have been linked to a neurodevelopmental disorder, a different clinical entity.

Somatic BAP1 Loss in Pathology

Loss of nuclear BAP1 staining by immunohistochemistry helps distinguish malignant mesothelioma from benign mesothelial proliferations, and BAP1 loss in uveal melanoma is associated with a higher risk of metastasis.

A somatic BAP1 finding in a tumour does not establish a germline syndrome; when the pattern of tumours or family history is suggestive, germline testing is the appropriate next step.

Surveillance and Emerging Treatment Angles

A confirmed germline BAP1 diagnosis leads to a surveillance programme — typically periodic skin and eye examination, abdominal imaging for renal and mesothelial tumours, and counselling about asbestos and ultraviolet exposure, which appear to interact with the genetic risk. Exact protocols are set by specialist services and are still being refined as penetrance data mature.

Therapeutically, BAP1-deficient tumours have been studied for sensitivity to EZH2 inhibitors, HDAC inhibitors and agents targeting the DNA-damage response, on the basis of the chromatin and repair roles of BAP1. These are investigational; standard treatment of a BAP1-related cancer currently follows the guidance for that tumour type.

Key Takeaways

• ·BAP1 is a chromatin-associated deubiquitinase that removes ubiquitin from histone H2A.
• ·Germline BAP1 loss predisposes to mesothelioma, uveal melanoma, renal cancer and distinctive skin tumours.
• ·Somatic BAP1 loss is a pathology marker and, in the right context, prompts germline evaluation.