Serial Profiling of Circulating Tumor DNA Identifies Dynamic Evolution of Clinically Actionable Genomic Alterations in High-Risk Neuroblastoma

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 gen...

Full description

Saved in:

Bibliographic Details
Published in:	Cancer discovery Vol. 12; no. 12; p. 2800
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	United States 02-12-2022
Subjects:	Biomarkers, Tumor - genetics Child Circulating Tumor DNA - genetics Disease Progression Genomics - methods High-Throughput Nucleotide Sequencing - methods Humans Mutation Neuroblastoma - genetics Receptor Protein-Tyrosine Kinases - genetics
Online Access:	Get more information
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. 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.
ISSN:	2159-8290
DOI:	10.1158/2159-8290.CD-22-0287