FOXA1突变改变了前列腺癌的先驱性活动,分化和表型
Elizabeth J Adams1, Wouter R Karthaus1, Elizabeth Hoover1
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|June 28, 2019
概括
转录因子FOXA1的突变改变了其DNA结合和开拓功能,影响了前列腺癌的进展. 这些变化可能导致功能增强或阻断正常细胞分化,从而促进瘤的侵袭性表型.
科学领域:
- 癌症学
- 分子生物学
- 遗传学
背景情况:
- 在特定的前列腺癌群体中发现了转录因子FOXA1的突变.
- 对于FOXA1突变的功能影响和功能增加或丧失的性质在很大程度上是未知的.
研究的目的:
- 分析人类前列腺癌中的FOXA1突变.
- 研究FOXA1突变对细胞行为和基因调节的功能后果.
主要方法:
- 来自3086个前列腺癌样本的FOXA1突变的注释.
- 使用小鼠前列腺器官和报告测试的功能测试.
- 通过测序 (ATAC-seq) 检测转化酶可访问的染色质,以评估染色质的可访问性和DNA结合性.
主要成果:
- 在FOXA1分叉域中确定了两个突变热点:Wing2和R219.
- 翼2突变发生在腺癌的所有阶段,而R219突变则在转移性神经内分泌瘤中增加.
- 在增殖试验中,FOXA1突变体表现出功能增强;R219突变体特别阻断光分化,并促进细胞间核/神经内分泌程序.
- ATAC-seq发现突变特异性的染色体变化和改变的FOXA1结合基因,其中R219突变更喜欢非正规基因.
结论:
- FOXA1突变显著改变其开拓性功能和DNA结合偏好.
- 这些变化破坏了正常的光上皮分化程序.
- 这些发现支持血统可塑性在前列腺癌进展中的作用.
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