Serial Profiling of Circulating Tumor DNA Identifies Dynamic Evolution of Clinically Actionable Genomic Alterations in High-Risk Neuroblastoma
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Abstract
Neuroblastoma evolution, heterogeneity, and resistance remain inadequately defined, suggesting a role for circulating tumor DNA (ctDNA) sequencing. To define the utility of ctDNA profiling in neuroblastoma, 167 blood samples from 48 high-risk patients were evaluated for ctDNA using comprehensive genomic profiling. At least one pathogenic genomic alteration was identified in 56% of samples and 73% of evaluable patients, including clinically actionable ALK and RAS–MAPK pathway variants. Fifteen patients received ALK inhibition (ALKi), and ctDNA data revealed dynamic genomic evolution under ALKi therapeutic pressure. Serial ctDNA profiling detected disease evolution in 15 of 16 patients with a recurrently identified variant—in some cases confirming disease progression prior to standard surveillance methods. Finally, ctDNA-defined ERRFI1 loss-of-function variants were validated in neuroblastoma cellular models, with the mutant proteins exhibiting loss of wild-type ERRFI1's tumor-suppressive functions. Taken together, ctDNA is prevalent in children with high-risk neuroblastoma and should be followed throughout neuroblastoma treatment. Significance: ctDNA is prevalent in children with neuroblastoma. Serial ctDNA profiling in patients with neuroblastoma improves the detection of potentially clinically actionable and functionally relevant variants in cancer driver genes and delineates dynamic tumor evolution and disease progression beyond that of standard tumor sequencing and clinical surveillance practices. See related commentary by Deubzer et al., p. 2727. This article is highlighted in the In This Issue feature, p. 2711
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A more recent study found that serial clinical ctDNA sampling in high-risk neuroblastoma helped monitor disease status and clonal tumor evolution.
“A more recent study demonstrated that serial clinical ctDNA sampling in patients with high-risk neuroblastoma (NBL) was useful for monitoring disease status and clonal tumor evolution.19”
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 [19]
Prior work has shown that liquid biopsies can detect ALK mutations in neuroblastoma patients to guide targeted therapy.
“Prior work has demonstrated the utility of liquid biopsies for detection of ALK mutations in patients with NBL to inform targeted therapies.19,26”
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 [19]
Multiple small-cohort studies in pediatric solid tumors, including rhabdomyosarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma, have shown associations between ctDNA burden and response to neoadjuvant therapy and disease relapse or recurrence.
“Multiple studies in small cohorts of patients with pediatric solid tumors, including rhabdomyosarcoma, NBL, EWS, and OS, have similarly shown associations between ctDNA burden and response to neoadjuvant therapy and disease relapse and recurrence.19,27,28”
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 [19]
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- Authors
- Bosse, K. R., Giudice, A. M., Lane, M. V., McIntyre, B., Schürch, P. M., Pascual-Pasto, G., Buongervino, S. N., Suresh, S., Fitzsimmons, A., Hyman, A., Gemino-Borromeo, M., Saggio, J., Berko, E. R., Daniels, A. A., Stundon, J., Friedrichsen, M., Liu, X., Margolis, M. L., Li, M. M., Tierno, M. B., Oxnard, G. R., Maris, J. M., & Mossé, Y. P.
- Affiliations
- Children's Hospital of Philadelphia (US)
- 1Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
- Foundation Medicine (United States) (US)
- Corresponding author
- Bosse, Kristopher R.
- ORCID
- Bosse, Kristopher R.
- Giudice, Anna Maria
- Lane, Maria V.
- McIntyre, Brendan
- Schürch, Patrick M.
- Pascual-Pasto, Guillem
- Buongervino, Samantha N.
- Suresh, Sriyaa
- Fitzsimmons, Alana
- Hyman, Adam
- Gemino-Borromeo, Maria
- Saggio, Jennifer
- Berko, Esther R.
- Daniels, Alexander A.
- Stundon, Jennifer
- Friedrichsen, Megan
- Liu, Xin
- Margolis, Matthew L.
- Li, Marilyn M.
- Tierno, Marni Brisson
- Oxnard, Geoffrey R.
- Maris, John M.
- Mossé, Yael P.
- Venue
- Cancer Discovery
- Published
- 2022-09-15
- Volume
- 12
- Issue
- 12
- Pages
- 2800-2819
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC9722579
- OpenAlex
- W4296038583
- Cited by
- 51
- References
- 60
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 12 · 2023: 13 · 2022: 2
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Damon Runyon Cancer Research Foundation (PST-07-16)
- National Cancer Institute (K08 CA230223, R35 CA220500, P01 CA217959)
- U.S. Department of Defense (CA190126P2)
- Giulio D'Angio Endowed Chair
- Patricia Brophy Endowed Chair
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Devaney Family Fund
- Band of Parents Foundation
- Laney's Legacy of Hope
- EVAN Foundation
- Topics
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Keywords
- neuroblastoma, circulating tumor DNA, liquid biopsy, tumor genomic evolution, ALK inhibition, RAS/MAPK pathway, clinically actionable variants, disease progression detection, tumor heterogeneity, high-risk neuroblastoma, childhood cancer
- MeSH terms
- Circulating Tumor DNA, Child, Humans, Mutation, Neuroblastoma, Biomarkers, Tumor, Disease Progression, Receptor Protein-Tyrosine Kinases, Genomics, High-Throughput Nucleotide Sequencing
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