Common Structural and Epigenetic Changes in the Genome of Castration-Resistant Prostate Cancer
Common Structural and Epigenetic Changes in the Genome of Castration-Resistant Prostate Cancer
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DOI：
10.1158/0008-5472.can-11-2079
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发表时间：
2012-02-01
期刊：
影响因子：
11.2
通讯作者：
Paris, Pamela L.
中科院分区：
文献类型：
--
作者：
Friedlander, Terence W.;Roy, Ritu;Paris, Pamela L.
原发性前列腺癌向去势抵抗性前列腺癌（CRPC）的进展与许多遗传和表观遗传改变有关，这些改变被认为可以促进转移部位的生存。在这项研究中，我们研究了CRPC中基因拷贝数和CpG甲基化状态，以深入了解在这种晚期前列腺癌中活跃的特定病理生理途径。我们的分析定义并验证了495个基因在CRPC中表现出基因拷贝数的显著差异，包括雄激素受体（AR）的增加和PTEN和视网膜母细胞瘤1 （RB1）的减少。存在或不存在AR基因扩增的肿瘤之间存在显著的拷贝数差异，包括在AR基因未扩增的肿瘤中常见的AR抑制因子缺失。RB1和HSD17B2经常同时发生基因甲基化和等位基因缺失，其中HSD17B2参与睾酮代谢。最后，与良性前列腺组织相比，大多数CRPC的基因组DNA高甲基化。我们的研究结果建立了一个综合的甲基化特征，结合表观基因组和结构分析，从而为CRPC中与规避激素治疗相关的基因组改变提供了见解。在这项综合基因组研究中发现的基因指向了CRPC的新药物靶点，CRPC是一种无法治愈的疾病，仍然是主要的治疗挑战。癌症Res;72 (3);616 - 25。(c) 2011年aacr。
Progression of primary prostate cancer to castration-resistant prostate cancer (CRPC) is associated with numerous genetic and epigenetic alterations that are thought to promote survival at metastatic sites. In this study, we investigated gene copy number and CpG methylation status in CRPC to gain insight into specific pathophysiologic pathways that are active in this advanced form of prostate cancer. Our analysis defined and validated 495 genes exhibiting significant differences in CRPC in gene copy number, including gains in androgen receptor (AR) and losses of PTEN and retinoblastoma 1 (RB1). Significant copy number differences existed between tumors with or without AR gene amplification, including a common loss of AR repressors in AR-unamplified tumors. Simultaneous gene methylation and allelic deletion occurred frequently in RB1 and HSD17B2, the latter of which is involved in testosterone metabolism. Lastly, genomic DNA from most CRPC was hypermethylated compared with benign prostate tissue. Our findings establish a comprehensive methylation signature that couples epigenomic and structural analyses, thereby offering insights into the genomic alterations in CRPC that are associated with a circumvention of hormonal therapy. Genes identified in this integrated genomic study point to new drug targets in CRPC, an incurable disease state which remains the chief therapeutic challenge. Cancer Res; 72(3); 616-25. (C) 2011 AACR.