Abstract
Abstract
Background
MYCN amplification is an established adverse feature in neuroblastoma, yet aggressive disease also occurs without MYCN amplification. We aimed to define progression-associated transcriptional states in MYCN-non-amplified neuroblastoma and examine their remodeling after therapy.
Methods
GSE49710/SEQC served as the discovery cohort (395 tumors after quality control), with independent evaluation in E-MTAB-8248 and TARGET-NBL. We further analyzed 112,843 tumor cells from paired diagnostic and post-therapy samples from 12 MYCN-non-amplified patients, using patients as the unit of inference.
Results
Aggressive tumors showed reduced neuronal differentiation and increased MYC/E2F and G2M activity. DNA-repair programs closely tracked proliferative signals, consistent with replication-associated stress rather than an independent dependency. Neuronal differentiation showed the most consistent direction across bulk cohorts, whereas proliferative associations varied in strength. After therapy, neuronal differentiation increased, whereas MYC/E2F, G2M, and ADRN-Proliferating states decreased. The MES fraction modestly increased, but the continuous ADRN/MES axis was not significant, supporting redistribution among multiple tumor-cell states rather than a uniform ADRN-to-MES transition.
Conclusions
MYCN-non-amplified neuroblastoma shows clinically relevant heterogeneity along a differentiation–proliferation axis. Therapy-associated partial reversal and multistate redistribution support prospective evaluation of transcriptional state in treatment-response and risk-stratification studies.