Somatic mutation and expression of BAP1 in hepatocellular carcinoma: an indicator for ferroptosis and immune checkpoint inhibitor therapies.
Somatic mutation and expression of BAP1 in hepatocellular carcinoma: an indicator for ferroptosis and immune checkpoint inhibitor therapies.
复制标题
肝细胞癌中 BAP1 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
DOI：
10.7150/jca.65574
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发表时间：
2022
影响因子：
3.9
通讯作者：
Li T
中科院分区：
文献类型：
--
作者：
Yan YC;Meng GX;Ding ZN;Liu YF;Chen ZQ;Yan LJ;Yang YF;Liu H;Yang CC;Dong ZR;Hong JG;Li T
BRCA 1相关蛋白1（BAP 1）是一种去泛素化酶，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BAP 1作为肿瘤抑制因子独立发挥作用。体细胞BAP1突变发生在各种恶性肿瘤中，但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。BAP 1在肝细胞癌（HCC）中的体细胞突变或表达改变是否影响癌发生或免疫原性仍不清楚。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。通过组织芯片的免疫组织化学进一步研究BAP 1与临床病理特征之间的关系。我们发现BAP 1高表达患者的预后明显差于BAP 1低表达患者，多因素分析显示BAP 1表达是预后不良的独立预后因素。BAP 1高表达的HCC与ESTIMATE评分低、肿瘤浸润性巨噬细胞增多、肿瘤突变负荷水平升高、微卫星不稳定性、新抗原计数以及HCC中程序性死亡配体1相关。此外，BAP 1突变的HCC显示促进铁凋亡的能力降低，并且BAP 1高表达与铁凋亡相关。总之，BAP 1的高表达反映了HCC中的免疫抑制和铁凋亡。BAP 1是一个很有前途的预后指标，肝癌的生存，并可能作为一个补充指标，为患者接受促铁蛋白沉积治疗或免疫治疗。
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.