质瘤高突变的机制和治疗影响
Mehdi Touat1,2,3, Yvonne Y Li4,5, Adam N Boynton4,6
1Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. mehdi.touat@gmail.com.
Nature
|April 24, 2020
概括
质瘤的高瘤突变负担源于DNA修复缺陷. 化疗可以驱动这种突变, 但它不能改善免疫疗法对这些侵袭性脑瘤的反应.
科学领域:
- 癌症学
- 遗传学
- 癌症研究
背景情况:
- 在质瘤中观察到高瘤突变负担 (超突变).
- 超突变的发展机制及其与免疫疗法反应的联系尚不清楚.
研究的目的:
- 在10294个质瘤中全面分析突变负荷和特征的分子决定因素.
- 了解导致质瘤高突变的途径及其对治疗反应的影响.
主要方法:
- 在10294个质瘤中分析突变负荷和特征的分子决定因素.
- 在MMR缺乏细胞中使用temozolomide诱导的损伤进行突变特征的实验回顾.
- 单细胞全基因组测序以确定微卫星突变.
主要成果:
- 发现了两种主要的突变途径: de novo (DNA聚合酶/ MMR基因缺陷) 和治疗后 (在使用temozolomide后获得的MMR缺陷).
- 缺乏MMR的质瘤缺乏T细胞透,异质性很高,存活率很低,对PD-1阻断的反应很低.
- 通过单细胞测序,在治疗后的高突变质瘤细胞中发现了微卫星突变.
结论:
- 化疗可以促进高突变质瘤群的产生.
- 化学疗法诱导的高突变不会增强对PD-1阻断免疫疗法的反应.
- 突变负担和突变特征是癌症的重要诊断工具.
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