Clinical Significance of TERT Promoter Mutations in Neuroblastoma

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.