BRCA1-associated Protein-1 (BAP1) is a protein discovered in a yeast screen in 1998 found to bind to the BRCA1 (the famous breast cancer susceptibility gene) protein 1. It is categorized as a ‘tumour suppressor’ which means it protects the human body from cancer in some way or another. BAP1 has been linked to a large number of cellular processes; however, we do not understand exactly which one or multiple of these processest result in its tumour suppressor function.
In 2010, Harbour et al found while investigating BAP1 somatic (tumour tissue) mutations in metastasizing uveal melanoma tumours that one patient had a germline frameshift in BAP1 2. Shortly thereafter, separately Abdel-Rahman et al, Popova et al, Testa et al and Wiesner et al started to categorize a novel tumour predisposition syndrome coined the BAP1 tumour predisposition syndrome (BAP1-TPDS) 3-6. We now have defined the expanded spectrum for this syndrome to include
- Uveal melanoma – https://www.cancer.gov/types/eye/patient/about-intraocular-melanoma-pdq
- Mesothelioma – https://www.cancer.gov/types/mesothelioma/patient/about-mesothelioma-pdq
- Cutaneous melanoma – https://www.cancer.gov/types/skin/patient/melanoma-treatment-pdq
- Renal cell carcinoma – https://www.cancer.gov/types/kidney/patient/kidney-treatment-pdq
- Meningioma – https://www.cancer.gov/types/brain/patient/adult-brain-treatment-pdq
- Cholangiocarcinoma – https://www.cancer.gov/types/liver/patient/about-bile-duct-cancer-pdq
- Basal cell carcinoma – https://www.cancer.gov/types/skin/patient/skin-treatment-pdq
- BAP1-inactivated melanocytic tumours, benign skin lesions
at varying levels of penetrance. This may not be the definitive spectrum, howevercurrently t these are the only tumours with sufficient evidence. It is also found to be somatically mutated in a larger spectrum of cancers as seen in the TCGA – https://portal.gdc.cancer.gov/genes/ENSG00000163930. Additionally, BAP1 expression or mutations have been linked to have prognostic value in multiple tumour types 2,7-14.
1-Jensen, D. E. et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16, 1097-1112 (1998).
2-Harbour, J. W. et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330, 1410-1413, doi:10.1126/science.1194472 (2010).
3-Abdel-Rahman, M. H. et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. Journal of medical genetics 48, 856-859, doi:10.1136/jmedgenet-2011-100156 (2011).
4-Popova, T. et al. Germline BAP1 mutations predispose to renal cell carcinomas. American journal of human genetics 92, 974-980, doi:10.1016/j.ajhg.2013.04.012 (2013).
5-Testa, J. R. et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nature genetics 43, 1022-1025, doi:10.1038/ng.912 (2011).
6-Wiesner, T. et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nature genetics 43, 1018-1021, doi:10.1038/ng.910 (2011).
7-Shankar, G. M. et al. Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro-oncology, doi:10.1093/neuonc/now235 (2016).
8-Arzt, L., Quehenberger, F., Halbwedl, I., Mairinger, T. & Popper, H. H. BAP1 protein is a progression factor in malignant pleural mesothelioma. Pathology oncology research : POR 20, 145-151, doi:10.1007/s12253-013-9677-2 (2014).
9-Baumann, F. et al. Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis 36, 76-81, doi:10.1093/carcin/bgu227 (2015).
10-Pulford, E., Huilgol, K., Moffat, D., Henderson, D. W. & Klebe, S. Malignant Mesothelioma, BAP1 Immunohistochemistry, and VEGFA: Does BAP1 Have Potential for Early Diagnosis and Assessment of Prognosis? Disease markers 2017, 1310478, doi:10.1155/2017/1310478 (2017).
11-Al-Shamsi, H. O. et al. BRCA-associated protein 1 mutant cholangiocarcinoma: an aggressive disease subtype. Journal of gastrointestinal oncology 7, 556-561, doi:10.21037/jgo.2016.03.05 (2016).
12-Hakimi, A. A. et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clinical cancer research : an official journal of the American Association for Cancer Research 19, 3259-3267, doi:10.1158/1078-0432.ccr-12-3886 (2013).
13-Kapur, P. et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal cell carcinoma: a retrospective analysis with independent validation. The Lancet. Oncology 14, 159-167, doi:10.1016/S1470-2045(12)70584-3 (2013).
14-Gossage, L. et al. Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma. Genes, chromosomes & cancer 53, 38-51, doi:10.1002/gcc.22116 (2014).