通过链接读取基因组测序揭示的驱动割抵抗性前列腺癌的结构变化
Srinivas R Viswanathan1, Gavin Ha1, Andreas M Hoff2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
Cell
|June 19, 2018
概括
与初级前列腺癌不同,转移性抵抗割的前列腺癌 (mCRPC) 经常出现AR位部重组,包括AR增强剂的并列重复. 这些发现揭示了复杂的mCRPC基因组学和潜在的治疗点.
科学领域:
- 基因组学
- 癌症学
- 前列腺癌研究
背景情况:
- 转移性抵抗割的前列腺癌 (mCRPC) 是前列腺癌死亡的主要原因.
- 对mCRPC的全基因组测序 (WGS) 研究有限,阻碍了对其基因组的理解.
- 识别mCRPC的基因组变化对于开发有效治疗至关重要.
研究的目的:
- 通过全基因组测序来研究mCRPC的基因结构.
- 确定与mCRPC进展相关的反复发生的基因变异,特别是在非编码区域.
- 根据新的基因组发现,发现mCRPC的潜在治疗点.
主要方法:
- 在23个mCRPC活检样本上进行了链接读取全基因组测序 (WGS).
- 分析了86名mCRPC患者的无细胞DNA (cfDNA) 测序数据.
- 描述了复杂的基因组重组,专注于AR位点和增强器区域.
主要成果:
- 在大多数mCRPC病例中观察到常见和复杂的AR位点重组.
- 在70% - 87%的mCRPC病例中发现了高度复发的AR上游增强剂,明显高于原发性前列腺癌 (< 2%).
- 鉴定了一组由AR或MYC增强剂重复发生的病例,这些病例与CDK12无活化驱动的全基因组串联重复表型有关.
结论:
- 这项研究揭示了mCRPC的复杂和独特的基因组结构,特别是涉及AR位点的重组.
- 经常出现的增强剂重复是mCRPC治疗的潜在新疗法目标.
- 对非编码mCRPC基因组的进一步探索可能会揭示更多的复发性事件和治疗策略.
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