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通过利用cfDNA中的结构变异来跟踪卵巢癌患者药物耐药性的克隆演变

Marc J Williams^1,2, Ignacio Vázquez-García^1,2,3, Grittney Tam⁴

¹Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

bioRxiv : the preprint server for biology

|September 4, 2024

概括

高度血清性卵巢癌 (HGSOC) 的耐药性往往来自于在治疗期间扩张的先前存在的克隆. 使用无细胞DNA (cfDNA) 追踪瘤进化,发现多克隆性耐药性,经常由高适应性克隆主导,影响治疗选择.

科学领域:

基因组学就是基因组学.
癌症生物学癌症生物学
进化医学是一种进化医学.

背景情况:

药物耐药性是治疗失败的首要原因在高度血清性卵巢癌 (HGSOC).
驱动瘤进化到耐药状态的机制仍然不太清楚.
在体内跟踪克隆进化对于理解耐药性发展至关重要.

研究的目的:

在全身疗法下研究HGSOC的克隆进化.
确定与药物耐药性相关的基因组特征和进化轨迹.
评估无细胞DNA (cfDNA) 对于监测治疗反应和耐药性的有用性.

主要方法:

结合单细胞全基因组测序与纵向cfDNA分析.
开发了一种cfDNA混合捕获和深度测序方法,利用克隆特异性的结构变异作为条形码.
应用了人口遗传学赖特-费舍尔模型来分析进化轨迹.

主要成果:

在HGSOC中耐药性往往是多克隆的,但可以由单一的高适应性克隆主导,减少复发时的多样性.
耐药克隆经常表现出瘤基因的放大 (例如,CCNE1,RAB25,NOTCH3,ERBB2).
进化轨迹表明药物诱导的积极选择;像EMT和VEGF上调调节这样的先前存在的状态与耐药性相关.

结论:

在HGSOC中,耐药克隆通常在诊断时已经存在,并经历了剧烈的扩张,改变了复发成分.
使用cfDNA和单细胞测序来追踪克隆进化,有助于理解患者特异性抗性动态.
这种方法有可能在HGSOC中指导适应性治疗决策.

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