在高危神经母细胞瘤中通过基因组重组激活端粒酶
Martin Peifer1,2, Falk Hertwig2,3, Frederik Roels2,3
1Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
在高危神经母细胞瘤中,基因组重组在端粒酶逆转录酶基因 (TERT) 附近激活其表达,导致不良结果. 这种端粒酶激活是这些侵袭性儿科癌症的重要驱动因素.
科学领域:
- 癌症学
- 遗传学
- 分子生物学
背景情况:
- 神经母细胞瘤是同情神经系统的儿童癌症.
- 高危神经母细胞瘤的预后不佳,
研究的目的:
- 研究高危神经母细胞瘤的分子基础.
- 确定与神经母细胞瘤不良结果相关的新基因变异.
主要方法:
- 全基因组测序56个神经母细胞瘤 (39个高风险,17个低风险).
- 在较大的队列中对基因组重组的分析 (n=217).
- 细胞系和瘤中的基因表达和端粒长度分析.
主要成果:
- 仅在高危神经母细胞瘤 (31%) 中,在TERT基因附近发现了5p15.33的复发性基因组重组.
- 这些重组导致了大量的TERT转录上调,并与特别糟糕的结果有关.
- 通过重新排列或MYCN放大,TERT激活和替代的端粒延长是不同高风险神经母细胞瘤子组的关键端粒维持机制.
结论:
- 在高危神经母细胞瘤中,基因组上下文重塑取消了TERT转录沉默.
- 端粒酶激活是这些瘤中很大一部分转化的核心机制.
- TERT重组定义了一个临床相关的高风险神经母细胞瘤子组.
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