Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.
Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.
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DOI：
10.1038/nm.4045
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发表时间：
2016-03
期刊：
影响因子：
82.9
通讯作者：
Demichelis F
中科院分区：
文献类型：
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作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
前列腺癌对雄激素受体(AR)导向治疗的抵抗机制日益得到认可，涉及上皮可塑性，其中肿瘤细胞表现出低表达或不表达AR，通常具有神经内分泌特征。这些“替代”耐药细胞状态的病因学和分子基础仍不完全清楚。在这里，通过分析患者转移性活检的整个外显子组测序数据，我们观察到抗去势腺癌(CRPC-ADEO)和神经内分泌组织学(CRPC-NE)之间存在显著的基因组重叠；对系列进展样本的分析指出了一个与差异克隆进化最一致的模型。全基因组DNA甲基化显示CRPC-NE和CRPC-Adeno之间存在显著的表观遗传学差异，并将具有AR非依赖性临床特征的CRPC-Adeno病例命名为CRPC-NE，提示表观遗传修饰物可能在这种耐药状态的诱导和/或维持中发挥作用。这项研究支持通过不同的克隆进化出现一种替代的、“AR无关”的细胞状态，作为晚期前列腺癌治疗抵抗的机制。
An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, wherein tumor cells demonstrate low to absent AR expression and often neuroendocrine features. The etiology and molecular basis for these “alternative” treatment-resistant cell states remain incompletely understood. Here, by analyzing whole exome sequencing data of metastatic biopsies from patients, we observed significant genomic overlap between castration resistant adenocarcinoma (CRPC-Adeno) and neuroendocrine histologies (CRPC-NE); analysis of serial progression samples points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation revealed marked epigenetic differences between CRPC-NE and CRPC-Adeno that also designated cases of CRPC-Adeno with clinical features of AR-independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, “AR-indifferent” cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.