Telomere Maintenance Mechanisms in a Cohort of High-Risk Neuroblastoma Tumors and Its Relation to Genomic Variants in the TERT and ATRX Genes.

Simple Summary: Immortalization is a hallmark of malignant tumors, including in pediatric cancer neuroblastoma, where it is associated with an adverse prognosis. In this study, we characterized a Swedish neuroblastoma cohort with the focus on telomere maintenance mechanisms (TMMs), i.e., MYCN amplification and the juxtapositioning of TERT and ATRX aberrations. We show a strong correlation between ATRX aberrations and ALT and that aberrations affecting ATRX or TERT are enriched in high-risk cases with 11q deletion. This study, thereby, supports the need for further advancement of TMM-targeted therapies for this subgroup of neuroblastoma patients. Tumor cells are hallmarked by their capacity to undergo unlimited cell divisions, commonly accomplished either by mechanisms that activate TERT or through the alternative lengthening of telomeres pathway. Neuroblastoma is a heterogeneous pediatric cancer, and the aim of this study was to characterize telomere maintenance mechanisms in a high-risk neuroblastoma cohort. All tumor samples were profiled with SNP microarrays and, when material was available, subjected to whole genome sequencing (WGS). Telomere length was estimated from WGS data, samples were assayed for the ALT biomarker c-circles, and selected samples were subjected to methylation array analysis. Samples with ATRX aberration in this study were positive for c-circles, whereas samples with either MYCN amplification or TERT re-arrangement were negative for c-circles. Both ATRX aberrations and TERT re-arrangement were enriched in 11q-deleted samples. An association between older age at diagnosis and 1q-deletion was found in the ALT-positive group. TERT was frequently placed in juxtaposition to a previously established gene in neuroblastoma tumorigenesis or cancer in general. Given the importance of high-risk neuroblastoma, means for mitigating active telomere maintenance must be therapeutically explored. [ABSTRACT FROM AUTHOR]