BAP1

Mutations in the BAP1 gene cause BAP1 tumor predisposition syndrome. People with this condition have an increased risk of developing many types of noncancerous (benign) and cancerous (malignant) tumors, particularly certain tumors of the skin (atypical Spitz tumors, cutaneous melanoma, and basal cell carcinoma); eyes (uveal melanoma); kidneys (clear cell renal cell carcinoma); and a tissue called the mesothelium that lines the chest, abdomen, and internal organs (malignant mesothelioma). Researchers are still determining whether other forms of cancer are linked to BAP1 tumor predisposition syndrome.

Affected individuals inherit a mutation in one copy of the BAP1 gene. These mutations, which are present in essentially every cell of the body, are classified as germline mutations. Most germline BAP1 gene mutations lead to an abnormally short BAP1 protein that is likely broken down prematurely. Other germline mutations change single protein building blocks (amino acids) in the BAP1 protein and likely impair its function. In most cases, a second, non-inherited (somatic) mutation occurs in the normal copy of the gene in cells that give rise to tumors. Together, the germline and somatic mutations lead to a loss of BAP1 protein function in tumor cells.

Reduction or loss of this protein's function likely prevents the removal of ubiquitin molecules from certain proteins. Although it is unclear exactly how changes in BAP1 function lead 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.

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Somatic BAP1 gene mutations have been found in uveal melanoma, malignant mesothelioma, and clear cell renal cell carcinoma tumors in the absence of a germline BAP1 gene mutation. In these cases, the cancers occur in people with no family history of the cancer and are considered sporadic. Affected individuals do not develop additional tumor types associated with BAP1 tumor predisposition syndrome (described above).