Division on Genitourinary Medical Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA.
Cancer Res. 2012 Feb 1;72(3):616-25. doi: 10.1158/0008-5472.CAN-11-2079. Epub 2011 Dec 7.
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.
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，这些改变被认为促进了转移部位的存活。在这项研究中，我们研究了 CRPC 中的基因拷贝数和 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 个在 CRPC 中表现出显著基因拷贝数差异的基因，包括雄激素受体 (AR) 的增加和 PTEN 和视网膜母细胞瘤 1 (RB1) 的丢失。在有或没有 AR 基因扩增的肿瘤之间存在显著的拷贝数差异，包括 AR 未扩增肿瘤中 AR 抑制剂的常见丢失。RB1 和 HSD17B2 中经常同时发生基因甲基化和等位基因缺失，后者参与睾酮代谢。最后，与良性前列腺组织相比，大多数 CRPC 的基因组 DNA 呈超甲基化状态。我们的发现建立了一个全面的甲基化特征，将表观基因组和结构分析结合在一起，从而深入了解与激素治疗逃避相关的 CRPC 中的基因组改变。在这项综合基因组研究中鉴定的基因指向了 CRPC 的新药物靶点，这是一种无法治愈的疾病状态，仍然是主要的治疗挑战。
