The Genetic Basis of the Divergent Clinical Courses in Neuroblastoma

Comprehensive profiling of genomic alterations and integration of this data with other molecular and clinical information in recent years has substantially advanced our understanding of the genetic basis underlying the disparate disease courses of neuroblastoma. While the overall mutational burden in neuroblastoma is low, as in other pediatric tumors, it was found that genomic alterations affecting key regulators of telomere maintenance occur in the vast majority of high-risk cases. Amplification of the transcription factor MYCN or genomic rearrangements of the TERT locus are found in most high-risk tumors, both leading to induction of telomerase expression. In another substantial fraction of high-risk neuroblastoma, telomeres are maintained by the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway, which is associated with inactivating mutations of the ATRX gene. By contrast, such alterations are invariably lacking in low-risk neuroblastoma, suggesting that absence of telomere maintenance and consecutive lack of cellular immortality may cause spontaneous regression and differentiation. In addition, oncogenic mutations have been found in the gene ALK, encoding for a receptor tyrosine kinase, in roughly 10% of neuroblastoma cases, and ALK inhibitory therapies are currently implemented in neuroblastoma treatment. Recurrent alterations are also detected in genes related to the RAS/MAPK and the p53 pathways. Integration of the diverse genomic information revealed that activation of telomere maintenance is the primary determinant of the clinical phenotype, whereas other alterations increase tumor aggressiveness only if telomere maintenance is present. This chapter summarizes the genomic alterations underlying the divergent courses of neuroblastoma, highlighting the pivotal role of telomere maintenance in this disease.