Natasha Persaud, Gunes Gundem, Brian H Kushner, Marc Ladanyi, Neerav Shukla, Shakeel Modak
{"title":"Clinical Significance of <i>TERT</i> Promoter Mutations in Neuroblastoma.","authors":"Natasha Persaud, Gunes Gundem, Brian H Kushner, Marc Ladanyi, Neerav Shukla, Shakeel Modak","doi":"10.1200/PO-25-00074","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong><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.</p><p><strong>Conclusion: </strong><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.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500074"},"PeriodicalIF":5.6000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12252578/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JCO precision oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1200/PO-25-00074","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/10 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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