Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer.
Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer.
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DOI：
10.1158/2159-8290.cd-19-1220
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发表时间：
2020-08
期刊：
影响因子：
28.2
通讯作者：
Gaudino G
中科院分区：
文献类型：
--
作者：
Carbone M;Harbour JW;Brugarolas J;Bononi A;Pagano I;Dey A;Krausz T;Pass HI;Yang H;Gaudino G
在200多个BAP 1突变家族中，几乎所有遗传了BAP 1突变等位基因的个体在其一生中都会发生一种或多种恶性肿瘤，主要是葡萄膜和皮肤黑色素瘤、间皮瘤和透明细胞肾细胞癌。这些癌症类型也是那些，当它们零星发生时，更有可能携带体细胞双等位基因BAP 1突变。机制研究表明，BAP 1的肿瘤抑制功能与其在细胞核中的双重活性有关，在细胞核中，它参与各种过程，包括DNA修复和转录，在细胞质中，它调节细胞死亡和线粒体代谢。肿瘤抑制中的BAP 1活性是细胞类型和环境依赖性的。BAP 1已成为多种癌症类型的关键肿瘤抑制因子，当在生殖系和体细胞中突变时，易诱发肿瘤发展。此外，BAP 1已成为基因-环境相互作用的关键调节因子。
Among more than 200 BAP1-mutant families affected by the “BAP1 cancer syndrome,” nearly all individuals inheriting a BAP1 mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic BAP1 mutations. Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual activity in the nucleus, where it is implicated in a variety of processes including DNA repair and transcription, and in the cytoplasm, where it regulates cell death and mitochondrial metabolism. BAP1 activity in tumor suppression is cell type– and context-dependent. BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically. Moreover, BAP1 has emerged as a key regulator of gene–environment interaction.