BAP1

BRCA1-Associated Protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase expressed in the nucleus (and perhaps also cytoplasm) of normal cells. BAP1 is a tumor suppressor and part of a complex that removes ubiquitin tags inhibiting protein break down. This affects many cellular and molecular processes including DNA damage repair, cell cycle control, chromatin modification, programmed cell death and immune response. Germline and somatic mutations in the BAP1 gene commonly occur in a variety of aggressive cancers, predominantly uveal melanoma, cutaneous melanoma, malignant mesothelioma and renal cell carcinoma.  Germline mutations (tumour predisposition syndrome; BAP1-TPDS) induce high risk of hereditary cancer. BAP1 alterations are characterized by loss of nuclear BAP1 protein expression.  

IHC for BAP1 is primarily used to identify cutaneous BAP1-inactivated melanocytic tumours (BIMT), differentiating uveal metastatic melanomas from cutaneous melanomas and differentiation of malignant mesothelioma and reactive mesothelial proliferation. Uveal metastatic melanomas have been reported to show BAP1 mutations in 77-84%, compared to 5% in cuteanous melanomas. BAP1 IHC has become a central biomarker in the diagnosis of mesothelial entities as 50-70% of epithelioid mesothelioma have BAP1 gene mutations (rarer in the sarcomatoid subtype). BAP1 mutations and associated protein alterations (loss of nuclear expression) are also seen in mesothelioma in situ lesions, but not reported in reactive mesothelium.       

At present it is recommended to use both external and internal tissue controls for BAP1. The external tissue controls can be used to monitor the IHC test reproducibility and give information on basic level of analytical sensitivity and specificity. Colon/appendix and tonsil can be recommended as positive and negative tissue controls for BAP1. In these tissues, virtually all nuclei should show an at least weak but distinct nuclear staining reaction. The cytoplasmic compartment of all cells should be negative or only display a weak diffuse staining reaction not compromising the read-out of nuclear BAP1 expression. In addition, it is of utmost importance that stromal cells and lymphocytes are used as internal positive controls in the interpretation of loss of nuclear BAP1 expression in cancer tissues. A reliable interpretation of the results in the tumor directly depends on clear demonstration of the internal positive control and if both entities negative the IHC test is not conclusive.