Clinical Significance of <i>TERT</i> Promoter Mutations in Neuroblastoma.

Abstract

Telomere maintenance mechanisms including <i>MYCN</i> amplification (<i>MYCN-</i>A) (via upregulated telomerase reverse transcriptase [<i>TERT</i>] expression), <i>TERT</i> rearrangements (<i>TERT</i>-RA), and <i>ATRX</i> mutations confer neoplastic immortality in neuroblastoma (NB) cells. Clinical characterization of patients with NB harboring activating somatic <i>TERT</i> promoter point mutations (<i>TERT</i>-PM) in NB may improve stratification. To identify <i>TERT</i>-PM and <i>TERT</i>-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. <i>TERT</i>-PM and <i>TERT</i>-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 <i>TERT</i>-PM and <i>TERT</i>-RA, respectively. <i>TERT</i>-PM were located at canonical hotspots (C228T [16/17] and C250T [1/17]) and were concurrent with <i>MYCN-</i>A in 9 of 17 (53%). By contrast, <i>MYCN</i>-A occurred in 1 of 31 <i>TERT</i>-RA tumors. Most patients with <i>TERT</i>-PM had stage M (94%) and high-risk NB (HR-NB) (81%) at diagnosis. Twenty-eight patients with <i>TERT</i>-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 <i>TERT</i>-PM and <i>TERT</i>-RA, respectively. The median progression-free (PFS) and overall survival (OS) were 9.7 ± 1.2 and 16.5 ± 2 months for patients with <i>TERT</i>-PM. Corresponding PFS/OS for patients with <i>TERT</i>-RA were 20 ± 6.4/56.8 ± 8.6 months (<i>P</i> = .015 for OS). Excluding <i>MYCN</i>-A status produced no significant survival difference (<i>P</i> > .1) between the two groups. CNS relapse occurred in 11 of 31 (35%) patients with <i>TERT</i>-RA versus 1 of 17 (6%) patients with <i>TERT</i>-PM. <i>TERT</i>-PM is rarer than <i>TERT</i>-RA but both are associated with HR-NB and poor prognosis. <i>MYCN-</i>A frequently co-occurs with <i>TERT</i>-PM and might represent an ultra-high-risk subset of patients.