"THE ENDS IN THE BEGINNINGS" age-related mechanisms of Telomere maintenance in pediatric and AYA-group Neuroblastoma.

This review focuses on the different Telomere Maintenance Mechanisms (TMMs), which take place in High-Risk Neuroblastoma (HR-NB) and vary according to age: 1. Reactivation of Telomerase (TEL+) in approximately 70-75 % of cases and 2. Alternative Lengthening of Chromosomes (ALT+) present in 25-30 % -mostly older-cases. ALT+ is based on homologous recombination and replication, but it is poorly understood. A seminal paper by Cheung et al. at MSKCC in 2012 initially discovered a skewed distribution of ALT+ pathway, with 0 % incidence in Infants and 100 % presence in the Adolescent/ Young Adults (AYA) group. This is critically evaluated and corrected in a less dichotomized fashion, thanks to more sophisticated NGS technologies. In contrast to the current interpretation for the skewed values -i.e. that aging creates very different oncogene dependencies, leading to different clonal expansions- this analysis underlines that (similarly to what happens in childhood leukemia/lymphoma) aging in neural crest cells causes remodelling of nuclear chromatin sites. Therefore, different genomic sites are susceptible to mutagenesis/rearrangements according to patients age and to clastogenic events. This second explanation better fits intra- and inter-tumor heterogeneity (TH) and the Micro-Foci inducing Virus (MFV) model as a clastogenic hit. Special discussion is on ATRX mutations of the ALT+ pathway, since very recent work from the Netherlands suggests that it may affect ribosomal genes and biogenesis. Previous work from the author showed that MFV may cause such ALT+ pathways as well as the reactivation of the Telomerase (hTERT) and that the target of GD2 immunotherapy corresponds indeed the MFV immediate-receptor.