JCO Precis Oncol. 2025 Jul;9:e2500074. doi: 10.1200/PO-25-00074. Epub 2025 Jul 10.
ABSTRACT
PURPOSE: Telomere maintenance mechanisms including MYCN amplification (MYCN-A) (via upregulated telomerase reverse transcriptase [TERT] expression), TERT rearrangements (TERT-RA), and ATRX mutations confer neoplastic immortality in neuroblastoma (NB) cells. Clinical characterization of patients with NB harboring activating somatic TERT promoter point mutations (TERT-PM) in NB may improve stratification.
METHODS: To identify TERT-PM and TERT-RA, tumors were profiled by the Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets targeted next-generation sequencing platform and whole-genome sequencing, respectively. Associated clinical outcomes were studied.
RESULTS: TERT-PM and TERT-RA were detected in 17 of 603 (2.8%) and 31of 168 (18.4%) tumors from individual patients, respectively. The median age at diagnosis was 32 (range, 15-79) and 48 (range, 3-168) months for TERT-PM and TERT-RA, respectively. TERT-PM were located at canonical hotspots (C228T [16/17] and C250T [1/17]) and were concurrent with MYCN-A in 9 of 17 (53%). By contrast, MYCN-A occurred in 1 of 31 TERT-RA tumors. Most patients with TERT-PM had stage M (94%) and high-risk NB (HR-NB) (81%) at diagnosis. Twenty-eight patients with TERT-RA had HR-NB (90%). After risk appropriate therapy, complete response was achieved in 7 of 17 (41%) and 17 of 31 (55%) patients with TERT-PM and TERT-RA, respectively. The median progression-free (PFS) and overall survival (OS) were 9.7 ± 1.2 and 16.5 ± 2 months for patients with TERT-PM. Corresponding PFS/OS for patients with TERT-RA were 20 ± 6.4/56.8 ± 8.6 months (P = .015 for OS). Excluding MYCN-A status produced no significant survival difference (P > .1) between the two groups. CNS relapse occurred in 11 of 31 (35%) patients with TERT-RA versus 1 of 17 (6%) patients with TERT-PM.
CONCLUSION: TERT-PM is rarer than TERT-RA but both are associated with HR-NB and poor prognosis. MYCN-A frequently co-occurs with TERT-PM and might represent an ultra-high-risk subset of patients.
PMID:40638875 | DOI:10.1200/PO-25-00074
