不同的克隆选择在复发时占主导地位
A Sorana Morrissy1,2, Livia Garzia1,2, David J H Shih1,2,3
1Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
Nature
|January 14, 2016
概括
针对癌症的治疗常常是失败的, 因为复发性瘤是基因进化的. 这项研究表明,在小鼠和人类中,主要的复发性瘤克隆是诊断时存在的小克隆,解释了治疗失败.
科学领域:
- 癌症学
- 基因组学
- 癌症生物学
背景情况:
- 针对性抗癌疗法旨在通过向癌症中的特定基因变异来改善生存率和降低毒性.
- 了解复发性瘤的遗传特征对于制定有效的治疗策略至关重要.
研究的目的:
- 在脑髓母细胞瘤治疗后,研究瘤复发的基因.
- 确定原发性瘤与复发性瘤之间是否存在基因差异.
- 确定复发性脑髓母细胞瘤的克隆起源,并解释向治疗的失败.
主要方法:
- 使用转子子驱动的功能性基因组小鼠模型,用"人性化"的体内治疗.
- 在33对人类诊断和治疗后脑髓母细胞瘤上进行全基因组测序.
- 在诊断和复发时分析了小鼠和人类髓母细胞瘤样本中的遗传事件.
主要成果:
- 复发的小鼠髓母细胞瘤与匹配的诊断样本中的遗传事件的重叠率很小 (< 5%).
- 人类髓母细胞瘤在治疗后表现出显著的遗传差异,< 12% 的诊断事件在复发时被保留.
- 在两种物种中复发时的主导克隆起源于诊断时存在的小克隆.
结论:
- 瘤复发是由先前存在的小克隆的克隆选择驱动的,这导致了与原始瘤的大量遗传差异.
- 在复发性瘤克隆中缺乏治疗点解释了向治疗的临床失败.
- 这些发现直接解释了先前临床试验中向治疗的无效性.
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