改变的染色体拓驱动SDH缺乏的GIST中的致癌程序
William A Flavahan1,2, Yotam Drier3,4,5, Sarah E Johnstone1,2
1Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nature
|November 1, 2019
概括
缺少突变的胃肠层瘤 (GIST) 的表观遗传变化通过改变基因组结构来激活瘤基因. 这项研究确定了这些癌症的新治疗点,特别是FGF受体抑制剂.
科学领域:
- 癌症学
- 表观遗传学
- 基因组学
背景情况:
- 虽然表观遗传异常在癌症中很常见,
- 一些胃肠层瘤 (GISTs) 呈现酸脱酶 (SDH) 缺乏的全球DNA超甲基化而不是激酶突变.
研究的目的:
- 调查表观遗传变化激活SDH缺乏GIST中的癌症程序的机制.
- 在不同的GIST亚型中绘制DNA甲基化,CTCF绝缘体,增强剂和染色体拓.
主要方法:
- 系统地绘制DNA甲基化,CTCF绝缘体,增强剂和染色体拓.
- 在GIST模型中通过CRISPR进行基因编辑.
- 建立和分析患者衍生的异种移植模型 (PDX).
主要成果:
- 缺少SDH的GIST显示DNA甲基化取代了数百个绝缘体的CTCF结合.
- 在SDH缺乏的GIST中失去特定的绝缘体会改变基因组拓,激活FGF4瘤基因.
- 一个来自患者的异种移植模型证实了表观遗传缺陷和对FGFR和KIT抑制的敏感性.
结论:
- 表观遗传变化,包括绝缘体缺陷和改变的基因组拓,可以在缺乏正规突变的GIST中驱动瘤发生.
- 这些发现突出了针对GIST异常表观遗传通路的新疗法,特别是使用FGFR抑制剂.
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