BAP1 loss

What is measured: loss of the BAP1 deubiquitinase, a tumour suppressor on 3p21. How: immunohistochemistry (loss of nuclear staining in tumour cells with retained staining in stromal and inflammatory cells), tumour sequencing, and germline testing when the patient is young, has more than one primary or a family history, because the BAP1 tumour predisposition syndrome brings mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma and distinctive BAP1-inactivated melanocytic skin tumours. Frequencies: about 60 percent of mesotheliomas (with CDKN2A and NF2 the three main lesions), about 45 percent of uveal melanomas (those with monosomy 3 and a class 2 expression profile), 10 to 15 percent of clear-cell renal cell carcinomas (worse than PBRM1-mutant) and 15 to 25 percent of small-duct intrahepatic cholangiocarcinomas. What a result changes: in mesothelioma, BAP1 loss with CDKN2A homozygous deletion on FISH proves malignancy over a reactive mesothelial proliferation, even on effusion cytology; in uveal melanoma it flags high metastatic risk, intensive liver surveillance and adjuvant trials; in renal cancer it is prognostic; a germline finding sets skin and eye examinations and imaging for the family; therapeutically, the EZH2 inhibitor tazemetostat had modest activity in BAP1-deficient mesothelioma, PARP and HDAC inhibitor trials continue, and immunotherapy may be more active in BAP1-mutant mesothelioma and kidney cancer, although the data are mixed. Where it matters: pleural and peritoneal mesothelioma, uveal melanoma, clear-cell RCC and intrahepatic cholangiocarcinoma.