Somatic mutation and expression of BAP1 in hepatocellular carcinoma: an indicator for ferroptosis and immune checkpoint inhibitor therapies

Abstract

BRCA1-Associated Protein 1 (BAP1) is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, and subsequent researches have revealed that BAP1 acts independently as a tumor suppressor. Somatic BAP1 mutations occur in various malignancies, but malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. Whether somatic mutation or expression alteration of BAP1 in hepatocellular carcinoma (HCC) influence carcinogenesis or immunogenicity is still unknown. In this study, we analyzed RNA expression, immune infiltration, survival and mutation data of HCC from The Cancer Genome Atlas databases. The association between BAP1 and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high BAP1 expression was significantly worse than that of patients with low BAP1 expression, and multivariate analyses revealed that BAP1 expression was an independent prognostic factor for poor prognosis. HCC with high BAP1 expression was associated with low ESTIMATE Score, recruitment of more tumor-infiltrating macrophage, and elevated levels of tumor mutation burden, microsatellite instability, neoantigen count, as well as programmed death-ligand1 in HCC. In addition, BAP1 mutated HCC showed reduced ability to promote ferroptosis and high BAP1 expression was correlated with ferroptosis. In conclusion, high BAP1 expression reflects immunosuppression and ferroptosis in HCC. BAP1 is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive ferroptosis-promoting therapy or immunotherapy.

Prognostic Model and Immune Infiltration of Ferroptosis Subcluster-Related Modular Genes in Gastric Cancer

“…Therefore, these results detailed the conditions and ways in which FRGs regulate GC development, which may be conducive to further study of immune escape surveillance. In addition, ferroptosis-related reactive oxygen species and iron uptake could lead to somatic nonsynonymous mutations and microsatellite instability, resulting in increasing immunogenicity and immune infiltrates [47,48], which was consistent with our findings.…”

The role of LINC01419 in regulating the cell stemness in lung adenocarcinoma through recruiting EZH2 and regulating FBP1 expression

“…LINC01419 overexpression inhibited FBP1 expression, and knockdown of LINC01419 promoted FBP1 expression. Studies have shown that FBP1 can inhibit the malignant progression of cancers such as hepatocellular carcinoma [35], cholangiocarcinoma [27], and breast cancer [36]. Dong et al showed that FBP1 deletion induces glycolytic processes, promotes EMT pathways in breast cancer cells as well as improves cell stemness in CSCs [36].…”

Modulation of the ubiquitin‐proteasome system by phytochemicals: Therapeutic implications in malignancies with an emphasis on brain tumors

“…127,128 Loss of functional BAP1 is associated with tumorigenesis or BAP1 cancer syndrome, which involves uveal melanoma, mesothelioma, renal cell carcinoma (RCC), HCC, cutaneous melanoma, and breast cancer. [129][130][131] Further, the BAP1 expression has been lower in human lung adenocarcinoma samples than in normal samples and is positively correlated with patient survival. Observations in an animal model of lung adenocarcinoma demonstrated the reduction of BAP1 level during tumor growth that was associated with the reduction of KELCH-ECH-associated protein 1 (Keap-1) expression and increased nuclear factor E2-related factor-2 (Nrf-2, a redox-sensitive transcription factor) activity as well as suppression of oxidative stress.…”

“…It also affects cell cycle proteins, mitochondrial function, cell survival, tumor metabolism, and immune responses 127,128 . Loss of functional BAP1 is associated with tumorigenesis or BAP1 cancer syndrome, which involves uveal melanoma, mesothelioma, renal cell carcinoma (RCC), HCC, cutaneous melanoma, and breast cancer 129–131 . Further, the BAP1 expression has been lower in human lung adenocarcinoma samples than in normal samples and is positively correlated with patient survival.…”