Copy-Number Aberrations in Circulating Tumor DNA Enable Diagnosis and Risk Stratification of Pediatric Neuroblastic Tumors.
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UNLABELLED: Low-pass whole-genome sequencing (LP-WGS) of circulating tumor DNA (ctDNA) is increasingly recognized for its utility in identifying somatic copy-number aberration (CNA). In this study, we analyzed LP-WGS ctDNA data from 73 pediatric patients with neuroblastic tumor and 11 healthy controls to explore diagnostic value of ctDNA CNA burden (including the genotypings) with a customized bioinformatics workflow. We found that a high baseline ctDNA CNA burden [tumor DNA fraction (TFx) ≥0.2%] was present in 36 of 41 patients (87.80%) with neuroblastoma, six of 22 patients (27.27%) with ganglioneuroblastoma, and three of 10 patients (30%) with ganglioneuroma. High baseline ctDNA CNA burden could predict high-risk neuroblastic tumors with an area under curve (AUC) of 0.95, sensitivity of 94.12%, and specificity of 100%. Frequent chromosomal copy-number changes, including chr17q gain, chr7 gain, chr3p loss, and chr11q loss, were found in ctDNA. Gain of chr17q demonstrated the highest diagnostic value with an AUC of 0.92, indicating strong sensitivity and specificity for detecting high-risk neuroblastic tumors. The homologous recombination deficiency score in the high- and intermediate-risk groups was significantly elevated compared with those in the low-/very low-risk group. The TFx levels and segmental alterations significantly decreased in patients with neuroblastic tumor who underwent chemotherapy, from median TFx = 13.82% before treatment to 0.24% after treatment (P < 0.0001). Our findings highlight the effectiveness of LP-WGS ctDNA CNA analysis as a promising approach for diagnosis and risk stratification of pediatric neuroblastic tumors and for monitoring chemotherapy response. Particularly, ctDNA analysis is minimally invasive, rapid, and cost-effective, which could bring additional benefits in pediatric practices. SIGNIFICANCE: Our results support the development of ctDNA CNA analysis as a robust and minimally invasive approach for early detection, molecular diagnosis, and risk stratification of peripheral neuroblastic tumors.