Detection of Somatic Structural Variants Enables Quantification and Characterization of Circulating Tumor DNA in Children With Solid Tumors.
Detection of Somatic Structural Variants Enables Quantification and Characterization of Circulating Tumor DNA in Children With Solid Tumors.
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DOI：
10.1200/po.17.00285
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发表时间：
2018
影响因子：
4.6
通讯作者：
Crompton BD
中科院分区：
文献类型：
--
作者：
Klega K;Imamovic-Tuco A;Ha G;Clapp AN;Meyer S;Ward A;Clinton C;Nag A;Van Allen E;Mullen E;DuBois SG;Janeway K;Meyerson M;Thorner AR;Crompton BD
液体活检作为新的疾病生物标志物正在迅速用于成人癌症。据报道，循环肿瘤 DNA (ctDNA) 水平与疾病负担成正比，与治疗反应相关并预测复发。然而，对于实体瘤儿科患者中 ctDNA 的检测频率，人们知之甚少。因此，我们开发了一种新一代测序方法来检测和量化最常见儿科实体瘤患者血液中的 ctDNA。 ctDNA 的检测需要对所研究的癌症类型中通常观察到的体细胞事件敏感的检测方法。在儿科实体瘤中，结构变异比复发性点突变更常见。我们采用超低通道全基因组测序方法来捕获拷贝数变异，并采用混合捕获测序分析来检测儿科患者液体活检样本中的易位。通过超低通道全基因组测序观察到的拷贝数变化能够检测骨肉瘤、神经母细胞瘤、肺泡横纹肌肉瘤和肾母细胞瘤患者的 ctDNA。在尤文肉瘤中，检测 EWSR1 易位是一种更灵敏的方法。对于在多个时间点采集样本的患者，ctDNA 水平的变化与治疗反应相对应。我们还发现，可以在 ctDNA 中检测到疾病特异性预后基因组生物标志物。这项研究表明，检测体细胞结构变异的液体活检方法非常适合儿童实体瘤。我们发现，患有最常见实体瘤恶性肿瘤的儿童具有可检测的 ctDNA 水平，这可用于跟踪疾病反应并识别疾病的基因组亚分类。目前正在努力对更多临床注释样本进行分析，以验证这些测定的临床用途。
Liquid biopsies are being rapidly used in adult cancers as new biomarkers of disease. Circulating tumor DNA (ctDNA) levels have been reported to be proportional to disease burden, correlate with treatment response, and predict relapse. However, little is known about how frequently ctDNA is detectable in pediatric patients with solid tumors. Therefore, we developed a next-generation sequencing approach to detect and quantify ctDNA in the blood of patients with the most common pediatric solid tumors. Detection of ctDNA requires assays sensitive to somatic events typically observed in the cancer type being studied. In pediatric solid tumors, structural variants are more common than recurrent point mutations. We adapted an ultralow passage whole-genome sequencing approach to capture copy number variants and a hybrid capture sequencing assay to detect translocations in liquid biopsy samples from pediatric patients. Copy number changes seen by ultralow passage whole-genome sequencing enabled detection of ctDNA in patients with osteosarcoma, neuroblastoma, alveolar rhabdomyosarcoma, and Wilms tumor. In Ewing sarcoma, detection of the EWSR1 translocation was a more sensitive approach. For patients with samples collected at multiple time points, changes in ctDNA levels corresponded to treatment response. We also found that disease-specific genomic biomarkers of prognosis were detectable in ctDNA. This study demonstrates that liquid biopsy approaches that detect somatic structural variants are well suited to pediatric solid tumors. We show that children with the most common solid tumor malignancies have detectable levels of ctDNA, which may be used to track disease response and identify genomic subclassifiers of disease. Efforts to profile larger collections of clinically annotated specimens are under way to validate the clinical use of these assays.