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.

中文翻译：

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BAP1在肝细胞癌中的体细胞突变和表达：铁死亡和免疫检查点抑制剂治疗的指标。

BRCA1 相关蛋白 1 (BAP1) 是一种去泛素化酶，发现与调节关键细胞通路的多蛋白复合物相关，随后的研究表明 BAP1 独立地作为肿瘤抑制因子起作用。体细胞 BAP1 突变发生在各种恶性肿瘤中，但由肿瘤抑制基因突变引起的恶性肿瘤具有无法解释的组织倾向。肝细胞癌 (HCC) 中 BAP1 的体细胞突变或表达改变是否影响致癌作用或免疫原性仍然未知。在这项研究中，我们分析了来自癌症基因组图谱数据库的 HCC 的 RNA 表达、免疫浸润、存活和突变数据。通过组织微阵列上的免疫组织化学进一步研究了 BAP1 与临床病理特征之间的关联。我们发现 BAP1 高表达患者的预后明显低于 BAP1 低表达患者，多因素分析显示 BAP1 表达是预后不良的独立预后因素。具有高 BAP1 表达的 HCC 与低 ESTIMATE 评分、更多肿瘤浸润巨噬细胞的募集以及 HCC 中肿瘤突变负荷、微卫星不稳定性、新抗原计数以及程序性死亡配体 1 水平升高有关。此外，BAP1 突变的 HCC 显示出促进铁死亡的能力降低，并且 BAP1 的高表达与铁死亡相关。总之，高 BAP1 表达反映了 HCC 中的免疫抑制和铁死亡。