Whole-genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the translation of ctDNA monitoring into vital preclinical PDX models has not been possible owing to low circulating blood volumes in small rodents. Here, we describe the longitudinal detection and monitoring of ctDNA from minute volumes of blood in PDX mice. We developed a xenograft Tumour Fraction (xTF) metric using shallow WGS of dried blood spots (DBS), and demonstrate its application to quantify disease burden, monitor treatment response and predict disease outcome in a preclinical study of PDX mice. Further, we show how our DBS-based ctDNA assay can be used to detect gene-specific copy number changes and examine the copy number landscape over time. Use of sequential DBS ctDNA assays could transform future trial designs in both mice and patients by enabling increased sampling and molecular monitoring.

中文翻译：

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使用异种移植模型中干血点的 ctDNA 纵向监测疾病负担和反应


循环肿瘤 DNA (ctDNA) 的全基因组测序 (WGS) 现在是预测治疗反应、疾病负担和疾病进展的临床重要生物标志物。然而，由于小型啮齿动物的循环血量较低，将 ctDNA 监测转化为重要的临床前 PDX 模型尚不可能。在这里，我们描述了 PDX 小鼠微量血液中 ctDNA 的纵向检测和监测。我们使用干血斑 (DBS) 的浅层 WGS 开发了异种移植肿瘤分数 (xTF) 指标，并在 PDX 小鼠的临床前研究中证明了其在量化疾病负担、监测治疗反应和预测疾病结果方面的应用。此外，我们展示了如何使用基于 DBS 的 ctDNA 检测来检测基因特异性拷贝数变化并检查拷贝数随时间的变化。使用连续 DBS ctDNA 检测可以通过增加采样和分子监测来改变小鼠和患者的未来试验设计。