Telomere Maintenance Mechanisms Define Clinical Outcome in High-Risk Neuroblastoma.

TitleTelomere Maintenance Mechanisms Define Clinical Outcome in High-Risk Neuroblastoma.
Publication TypeJournal Article
Year of Publication2020
AuthorsKoneru, B, Lopez, G, Farooqi, A, Conkrite, KL, Nguyen, TH, Macha, SJ, Modi, A, Rokita, JLynne, Urias, E, Hindle, A, Davidson, H, McCoy, K, Nance, J, Yazdani, V, Irwin, MS, Yang, S, Wheeler, DA, Maris, JM, Diskin, SJ, C Reynolds, P
JournalCancer Res
Volume80
Issue12
Pagination2663-2675
Date Published2020 Jun 15
ISSN1538-7445
KeywordsCell Line, Tumor, Child, Child, Preschool, Disease-Free Survival, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Infant, Male, Neoplasm Recurrence, Local, Neuroblastoma, RNA, Messenger, RNA-Seq, Telomerase, Telomere, Telomere Homeostasis, Whole Genome Sequencing, X-linked Nuclear Protein, Xenograft Model Antitumor Assays
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 covariates in 134 neuroblastoma patient samples at diagnosis. In addition, we assessed TMM in neuroblastoma cell lines ( = 104) and patient-derived xenografts ( = 28). ALT was identified in 23.4% of high-risk neuroblastoma tumors and genomic alterations in were detected in 60% of ALT tumors; 40% of ALT tumors lacked genomic alterations in known ALT-associated genes. Patients with high-risk neuroblastoma were classified into three 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; < 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 OS (even after relapse) and two cohorts of patients with poor survival that have distinct molecular therapeutic targets. SIGNIFICANCE: These findings assess telomere maintenance mechanisms with TERT mRNA and the ALT DNA biomarker C-circles to stratify neuroblastoma into three groups, with distinct overall survival independent of currently used clinical risk classifiers.

DOI10.1158/0008-5472.CAN-19-3068
Alternate JournalCancer Res
PubMed ID32291317
PubMed Central IDPMC7313726
Grant ListR35 CA220500 / CA / NCI NIH HHS / United States
R01 CA204974 / CA / NCI NIH HHS / United States
R01 CA217251 / CA / NCI NIH HHS / United States
R01 CA221957 / CA / NCI NIH HHS / United States
U10 CA098543 / CA / NCI NIH HHS / United States
RC1 MD004418 / MD / NIMHD NIH HHS / United States
U10 CA098413 / CA / NCI NIH HHS / United States

Similar Publications