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Frequency and Prognostic Impact of ALK amplifications and mutations in the European Neuroblastoma Study Group (SIOPEN) High Risk Neuroblastoma trial (HRNBL-1)

Lookup NU author(s): Dr Nicholas Bown, Professor Deborah Tweddle



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


PURPOSEIn neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact.MATERIALS AND METHODSDiagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571).RESULTSGenomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome.CONCLUSIONGenetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.

Publication metadata

Author(s): Bellini A, Pötschger U, Bernard V, Lapouble E, Baulande S, Ambros PF, Auger N, Beiske K, Bernkopf M, Betts DR, Bhalshankar J, Bown N, de Preter K, Clément N, Combaret V, Font de Mora J, George SL, Jiménez I, Jeison M, Marques B, Martinsson T, Mazzocco K, Morini M, Mühlethaler-Mottet A, Noguera R, Pierron G, Rossing M, Taschner-Mandl S, Van Roy N, Vicha A, Chesler L, Balwierz W, Castel V, Elliott M, Kogner P, Laureys G, Luksch R, Malis J, Popovic-Beck M, Ash S, Delattre O, Valteau-Couanet D, Tweddle DA, Ladenstein R, Schleiermacher G

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Oncology

Year: 2021

Volume: 39

Issue: 30

Pages: 3377-3390

Print publication date: 20/10/2021

Online publication date: 11/06/2021

Acceptance date: 01/04/2021

Date deposited: 25/11/2021

ISSN (print): 0732-183X

ISSN (electronic): 1527-7755

Publisher: American Society of Clinical Oncology


DOI: 10.1200/JCO.21.00086

PubMed id: 3411554


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Funder referenceFunder name
Neuroblastoma UK, Cancer Research UK, Department of Health, Families against Neuroblastoma, Solving Kids' Cancer, and Action Medical Research/Great Ormond Street Hospital Charity
SiRIC/INCa (Grant INCa-DGOS-4654) and PHRC IC2007-09 grant.