Combined low-pass whole genome and targeted sequencing in liquid biopsies for pediatric solid tumors
Open accessAbstract
We designed a liquid biopsy (LB) platform employing low-pass whole genome sequencing (LP-WGS) and targeted sequencing of cell-free (cf) DNA from plasma to detect genome-wide copy number alterations (CNAs) and gene fusions in pediatric solid tumors. A total of 143 plasma samples were analyzed from 19 controls and 73 patients, including 44 bone or soft-tissue sarcomas and 12 renal, 10 germ cell, five hepatic, and two thyroid tumors. cfDNA was isolated from plasma collected at diagnosis, during and after therapy, and/or at relapse. Twenty-six of 37 (70%) patients enrolled at diagnosis without prior therapy (radiation, surgery, or chemotherapy) had circulating tumor DNA (ctDNA), based on the detection of CNAs from LP-WGS, including 18 of 27 (67%) patients with localized disease and eight of 10 (80%) patients with metastatic disease. None of the controls had detectable somatic CNAs. There was a high concordance of CNAs identified by LP-WGS to CNAs detected by chromosomal microarray analysis in the matching tumors. Mutations identified in tumor samples with our next-generation sequencing (NGS) panel, OncoKids®, were also detected by LP-WGS of ctDNA in 14 of 26 plasma samples. Finally, we developed a hybridization-based capture panel to target EWSR1 and FOXO1 fusions from patients with Ewing sarcoma or alveolar rhabdomyosarcoma (ARMS), respectively. Fusions were detected in the plasma from 10 of 12 patients with Ewing sarcoma and in two of two patients with ARMS. Combined, these data demonstrate the clinical applicability of our LB platform to evaluate pediatric patients with a variety of solid tumors.
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The observed decline across two independent analyte classes (ctDNA and miRNA) strengthens biological plausibility and supports the use of multi-analyte liquid biopsy strategies in pediatric sarcoma monitoring.
“Importantly, the observed decline across two independent analyte classes (ctDNA and miRNA) strengthens biological plausibility and supports the use of multi-analyte liquid biopsy strategies in pediatric sarcoma monitoring [36].”
From Circulating Tumor DNA and microRNA–Based Liquid Biopsy for Longitudinal Treatment Monitoring and Recurrence Prediction in Pediatric Sarcomas: A Prospective Cohort Study (2026) · cites this paper as [36]
The Results section, “LP-WGS reveals the presence of ctDNA prior to clinical recurrence” (page not provided), reports that ctDNA abnormalities in a patient with osteosarcoma became undetectable after therapy and that serial testing detected recurrence before imaging. The Discussion suggests serial liquid biopsies may help detect response and relapse. The paper does not report a parallel miRNA decline in pediatric sarcoma or establish that concordance between ctDNA and miRNA supports multi-analyte monitoring. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPrevious studies have found that children with solid tumors often have clinically relevant variants detected by ctDNA assays designed to capture common pediatric tumor copy number alterations and translocations.
“Previous studies have found that children with solid tumors have frequently detected variants of clinical relevance via ctDNA assays designed to capture common pediatric tumor CNAs and translocations.”
From Clinical Liquid Biopsy Testing for Detection of Actionable Genomic Alterations in Children and Young Adults With Advanced Solid Tumors on the GAIN Study (2026) · cites this paper as [23]
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A comprehensive overview of liquid biopsy applications in pediatric solid tumors
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“Importantly, the observed decline across two independent analyte classes (ctDNA and miRNA) strengthens biological plausibility and supports the use of multi-analyte liquid biopsy strategies in pediatric sarcoma monitoring [36].”
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- Authors
- Christodoulou, E., Yellapantula, V., O’Halloran, K., Xu, L., Berry, J. L., Cotter, J. A., Zdanowicz, A., Mascarenhas, L., Amatruda, J. F., Ostrow, D., Bootwalla, M., Gai, X., Navid, F., & Biegel, J. A.
- Affiliations
- Children's Hospital Los Angeles (US)
- University of Southern California (US)
- Corresponding author
- Biegel, Jaclyn A.
- ORCID
- Venue
- npj Precision Oncology
- Published
- 2023-02-20
- Volume
- 7
- Issue
- 1
- Pages
- 21-21
- ISSN
- 2397-768X (ISSN-L)
- PMC
- PMC9941464
- OpenAlex
- W4321376012
- Cited by
- 55
- References
- 39
- Citations by year
- 2026: 6 · 2025: 21 · 2024: 21 · 2023: 7
- FWCI
- 7.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- npj Precision Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Las Madrinas Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- liquid biopsy, low-pass sequencing, cell-free DNA, pediatric solid tumors, copy number alterations, gene fusion, Ewing sarcoma, alveolar rhabdomyosarcoma, circulating tumor DNA, gene panel, bone and soft tissue sarcoma, kidney cancer, germ cell tumors, liver tumors, thyroid tumors, tumor mutation detection
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