Circulating tumor DNA (ctDNA) monitoring, while sufficiently advanced to reflect tumor evolution in real time and inform cancer diagnosis, treatment, and prognosis, mainly relies on DNA that originates from cell death via apoptosis or necrosis. In solid tumors, chemotherapy and immune infiltration can induce spatially variable rates of cell death, with the potential to bias and distort the clonal composition of ctDNA. Using a stochastic evolutionary model of boundary-driven growth, we study how elevated cell death on the edge of a tumor can simultaneously impact driver mutation accumulation and the representation of tumor clones and mutation detectability in ctDNA. We describe conditions in which invasive clones are over-represented in ctDNA, clonal diversity can appear elevated in the blood, and spatial bias in shedding can inflate subclonal variant allele frequencies (VAFs). Additionally, we find that tumors that are mostly quiescent can display similar biases but are far less detectable, and the extent of perceptible spatial bias strongly depends on sequence detection limits. Overall, we show that spatially structured shedding might cause liquid biopsies to provide highly biased profiles of tumor state. While this may enable more sensitive detection of expanding clones, it could also increase the risk of targeting a subclonal variant for treatment. Our results indicate that the effects and clinical consequences of spatially variable cell death on ctDNA composition present an important area for future work.
循环肿瘤DNA（ctDNA）监测技术虽已较为成熟，能够实时反映肿瘤演化并指导癌症诊断、治疗及预后评估，但其主要依赖于细胞凋亡或坏死释放的DNA。在实体瘤中，化疗与免疫浸润可能诱导空间异质性的细胞死亡速率，这可能导致ctDNA的克隆组成产生偏差与失真。通过建立边界驱动生长的随机演化模型，我们研究了肿瘤边缘细胞死亡率升高如何同时影响驱动突变的累积、肿瘤克隆在ctDNA中的代表性以及突变检测灵敏度。我们描述了以下现象的发生条件：侵袭性克隆在ctDNA中过度呈现，血液中克隆多样性可能被高估，以及脱落过程的空间偏差会放大亚克隆变异等位基因频率（VAF）。此外，我们发现处于静息状态的肿瘤虽可能呈现类似偏差，但其检测难度显著增加，且可观测的空间偏差程度高度依赖于测序检测限。总体而言，我们的研究表明空间结构化的DNA脱落可能导致液体活检呈现高度偏倚的肿瘤状态图谱。虽然这可能提升对扩张克隆的检测灵敏度，但也可能增加针对亚克隆变异进行治疗的风险。我们的研究结果提示，空间异质性细胞死亡对ctDNA组成的影响及其临床意义，是未来需要重点探索的领域。
肿瘤(癌症)患者之家