Molecular mechanisms of maturation in neurogenic embryonal tumors of peripheral and central localization.

Abstract

Tumor maturation is a property of neuroblastomas but can also be observed in unique cases of primary brain malignancies. We hypothesized that the mechanisms of peripheral and central neurogenic tumor maturation could be similar. This study encompassed 19 cases of neuroblastoma and solitary cases of CNS tumors having undergone a morphologically verified maturation. The tumors were analyzed by sequencing and gene expression profiling. We revealed potential similarity of different tumor types upon maturation, associated with stimulated MAPK, PI3K-AKT-mTOR, and TrkA signaling and suppressed regulation of cell cycle and DNA replication and repair. Tumors completing maturation similarly showed enhanced immunogenicity. The levels of NTRK2 expression increased during maturation. Expression of NTRK1 and positive epigenetic regulators (SWI/SNF subunits) increased prior to maturation and decreased upon the differentiation completion. Expression of negative epigenetic regulators EZH2, HDAC10, HDAC2, and DNMT3A decreased in maturing tumors. These data suggest that central and peripheral neurogenic tumors are likely to have common maturation mechanisms. Molecular scenarios associated with neuroblastoma maturation could be: (1) TrkA signaling (seen in cases presenting in < 18-month-olds), or (2) altered expression of epigenetic regulators and transcription factors (seen in cases presenting in >18-month-olds); treatment-induced maturation of CNS malignancies could involve both scenarios.