In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10⁻⁵. The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care.

在肿瘤学的许多领域，我们缺乏追踪低负担疾病的敏感工具。尽管无细胞 DNA (cfDNA) 在检测癌症突变方面显示出希望，但我们发现低肿瘤分数 (TF) 和有限数量的 DNA 片段的结合限制了通过流行的深度靶向测序范例进行低疾病负担监测。我们推断，测序的广度可能会取代测序的深度，以克服 cfDNA 丰度的障碍。 cfDNA 的全基因组测序 (WGS) 允许超灵敏检测，利用在实体恶性肿瘤中观察到的数千个体细胞突变的累积信号，TF 检测灵敏度低至 10 ^-5 。 WGS 方法实现了动态肿瘤负荷跟踪和术后残留疾病检测，与不良结果相关。因此，我们提出了一个通过全基因组突变整合来监测 cfDNA 癌症的正交框架，实现超灵敏检测，克服 cfDNA 丰度的限制，并促进低疾病负担肿瘤护理中的治疗优化。