Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

• Autor(a) principal: Bellini, Angela
• Data de Publicação: 2021
• Outros Autores: Pötschger, Ulrike, Bernard, Virginie, Lapouble, Eve, Baulande, Sylvain, Ambros, Peter F., Auger, Nathalie, Beiske, Klaus, Bernkopf, Marie, Betts, David R., Bhalshankar, Jaydutt, Bown, Nick, de Preter, Katleen, Clément, Nathalie, Combaret, Valérie, Font de Mora, Jaime, George, Sally L., Jiménez, Irene, Jeison, Marta, Marques, Barbara, Martinsson, Tommy, Mazzocco, Katia, Morini, Martina, Mühlethaler-Mottet, Annick, Noguera, Rosa, Pierron, Gaelle, Rossing, Maria, Taschner-Mandl, Sabine, Van Roy, Nadine, Vicha, Ales, Chesler, Louis, Balwierz, Walentyna, Castel, Victoria, Elliott, Martin, Kogner, Per, Laureys, Geneviève, Luksch, Roberto, Malis, Josef, Popovic-Beck, Maja, Ash, Shifra, Delattre, Olivier, Valteau-Couanet, Dominique, Tweddle, Deborah A., Ladenstein, Ruth, Schleiermacher, Gudrun
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.18/7937
• topic: Neuroblastoma; ALK; Prognostic Impact; European Neuroblastoma Study Group; SIOPEN; Doenças Genéticas

Purpose: In 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 methods: Diagnostic 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). Results: Genomic 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. Conclusion: Genetic 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.