Epigenetic Liquid Biopsy Enables Universal Mutation-Agnostic Molecular Surveillance for High-Risk Neuroblastoma
Gal Mark, N.; Grunwald, A.; Gahramanov, V.; Hameiri-Grossman, M.; Shinderman-Maman, E.; Gaas, D.; Shichrur, K.; Chausky Barzakh, E.; Sever, A.; Amar, S.; Ash, S.; Birger, Y.; Izraeli, S.; Ebenstein, Y.; Berko, E. R.
Show abstract
Pediatric solid tumors present a challenge for precision oncology as most tumors harbor low mutational burden, limiting the applicability of standard mutation-based liquid biopsy approaches for molecular monitoring. To overcome this, we developed a mutation-independent liquid biopsy framework based on Oxford Nanopore Technology sequencing, utilizing robust DNA methylation-based biomarkers for detection and surveillance of high-risk neuroblastoma (HR-NBL), a common pediatric solid tumor. Comparative analysis of tumor-derived DNA methylation profiles against a comprehensive atlas of normal human cell types identified 72 NBL-specific differentially methylated regions (termed meNBLs). Integration of 25 selected meNBLs into the methylation atlas enabled quantitative deconvolution of NBL-derived cfDNA, outperforming copy number and mutation-based estimates. NBL-specific blood plasma-derived cfDNA was detected at diagnosis but not in healthy controls, absent during remission, and markedly elevated at relapse, even before clinical detection of disease recurrence. These findings establish methylation-based deconvolution as a robust, mutation-independent approach for cfDNA monitoring in HR-NBL.
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