Telomere Maintenance Mechanisms Define Clinical Outcome in High-Risk Neuroblastoma
- 14 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (12), 2663-2675
- https://doi.org/10.1158/0008-5472.can-19-3068
Abstract
Neuroblastoma is a childhood cancer with heterogeneous clinical outcomes. To comprehensively assess the impact of telomere maintenance mechanism (TMM) on clinical outcomes in high-risk neuroblastoma, we integrated the C-circle assay (a marker for alternative lengthening of telomeres (ALT)), TERT mRNA expression by RNA sequencing, whole genome/exome sequencing, and clinical co-variates in 134 neuroblastoma patient samples at diagnosis. In addition, we assessed TMM in neuroblastoma cell lines (n=104) and PDX (n=28). ALT was identified in 23.4% of high-risk neuroblastoma tumors and genomic alterations in ATRX were detected in 60% of ALT tumors; 40% of ALT tumors lacked genomic alterations in known ALT-associated genes. High-risk neuroblastoma patients were classified into 3 subgroups (TERT-high, ALT+, and TERT-low/non-ALT) based on presence of C-circles and TERT mRNA expression (above or below median TERT expression). Event-free survival was similar among TERT-high, ALT+, or TERT-low/non-ALT patients. However, overall survival (OS) for TERT-low/non-ALT patients was significantly higher relative to TERT-high or ALT patients (log-rank test; P < 0.01) independent of current clinical and molecular prognostic markers. Consistent with the observed higher OS in patients with TERT-low/non-ALT tumors, continuous shortening of telomeres and decreasing viability occurred in low TERT-expressing, non-ALT patient-derived high-risk neuroblastoma cell lines. These findings demonstrate that assaying TMM with TERT mRNA expression and C-circles provides precise stratification of high-risk neuroblastoma into three subgroups with substantially different OS: a previously undescribed TERT-low/non-ALT cohort with superior overall survival (even after relapse) and two cohorts of patients with poor survival that have distinct molecular therapeutic targets.Other Versions
Funding Information
- Cancer Prevention & Research Institute of Texas (RP170510)
- NCI (CA217251)
- NCI (CA221957)
- NCI (R01CA204974)
- NCI (R35CA220500)
- NIH (RC1MD004418)
- COG Alex's Lemonade Stand Foundation (CA98543, CA98413)
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