Abstract
BRCA1-Associated Protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase that has been established as a tumor suppressor, utilizing its deubiquitinating activity to regulate a number of processes including DNA damage repair, cell cycle control, chromatin modification, programmed cell death, and the immune response. Mutations in the BAP1 gene commonly result in a number of aggressive cancers; predominantly uveal melanoma, malignant mesothelioma, renal cell carcinoma, and cutaneous melanoma. Importantly, germline mutations in the BAP1 gene have been established as a novel tumor predisposition syndrome, conferring an increased risk of hereditary, early-onset cancers. Current treatment options for cancers with BAP1 alterations are limited to standard therapies. However, several therapeutic avenues have been proposed to specifically target BAP1 alterations in cancer. Molecularly targeted approaches include histone deacetylase inhibitors and EZH2 inhibitors to target the role of BAP1 in chromatin modification and transcriptional regulation, respectively. PARP inhibitors and platinum chemotherapy agents have the potential to target BAP1-altered tumors, due to the role of BAP1 in DNA damage repair. Lastly, emerging reports suggest that BAP1 alterations in cancer confer distinct immunogenic phenotypes that may be particularly susceptible to novel cancer immunotherapies. This review aims to present a concise and up to date report on the BAP1 gene in cancer, surveying its functional roles, characteristics and clinical manifestations. Furthermore, we highlight the established and emerging therapeutic options for BAP1-mutated cancers.
Highlights
BRCA1-Associated Protein 1 (BAP1), encoded by the BAP1 gene, was originally discovered in 1998 as a novel ubiquitin carboxy-terminal hydrolase, an enzyme responsible for removing ubiquitin from protein substrates [1]
Numerous research groups have revealed that BAP1 acts independently as a tumor sup pressor, utilizing its deubiquitinating activity to regulate proteins in volved in DNA damage repair, cellular differentiation, chromatin modulation, cell cycle control, and cell proliferation [2]
BAP1 is a multifaceted tumor suppressor gene that regulates a wide variety of processes that are implicated in cancer
Summary
BRCA1-Associated Protein 1 (BAP1), encoded by the BAP1 gene, was originally discovered in 1998 as a novel ubiquitin carboxy-terminal hydrolase, an enzyme responsible for removing ubiquitin from protein substrates [1]. (NCT02860286) Overall survival was significantly longer for patients with malignant mesothelioma and loss-of-function mutations in BAP1 and DNA repair genes compared with patients with no such mutations who were treated with platinum chemotherapy [65] Niraparib (NCT03207347) and olaparib (NCT03531840)—ongoing Phase II studies selecting for patients with BAP1 alterations and other DNA repair gene defects [67,68] Checkpoint blockade results in responses in ~20–30% of mesothelioma patients[52,53] Other chromatin remodeling genes similar to BAP1 have been associated with therapeutic response to Anti-PD1/PDL1 therapy [74] Immune checkpoint inhibitors alone, result in 5–15% response rates in uveal melanoma [44,47]. Given the immunological phenotypes of tumor cells deficient in BAP1 and recent studies that showcase inactivated chromatin re modelers as potential markers for immunotherapy response, further investigation into an association between BAP1 alterations and the immune response in cancer is warranted
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