PURPOSE: Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression. EXPERIMENTAL DESIGN: The frequency and type of ALK mutations, copy number gain, and expression were analyzed in a new series of 254 neuroblastoma tumors. Data from 455 published cases were used for further in-depth analysis. RESULTS: ALK mutations were present in 6.9% of 709 investigated tumors, and mutations were found in similar frequencies in favorable [International Neuroblastoma Staging System (INSS) 1, 2, and 4S; 5.7%] and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P = 0.087). Two hotspot mutations, at positions R1275 and F1174, were observed (49% and 34.7% of the mutated cases, respectively). Interestingly, the F1174 mutations occurred in a high proportion of MYCN-amplified cases (P = 0.001), and this combined occurrence was associated with a particular poor outcome, suggesting a positive cooperative effect between both aberrations. Furthermore, the F1174L mutant was characterized by a higher degree of autophosphorylation and a more potent transforming capacity as compared with the R1275Q mutant. Chromosome 2p gains, including the ALK locus (91.8%), were associated with a significantly increased ALK expression, which was also correlated with poor survival. CONCLUSIONS: ALK mutations occur in equal frequencies across all genomic subtypes, but F1174L mutants are observed in a higher frequency of MYCN-amplified tumors and show increased transforming capacity as compared with the R1275Q mutants.
PURPOSE: Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression. EXPERIMENTAL DESIGN: The frequency and type of ALK mutations, copy number gain, and expression were analyzed in a new series of 254 neuroblastoma tumors. Data from 455 published cases were used for further in-depth analysis. RESULTS:ALK mutations were present in 6.9% of 709 investigated tumors, and mutations were found in similar frequencies in favorable [International Neuroblastoma Staging System (INSS) 1, 2, and 4S; 5.7%] and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P = 0.087). Two hotspot mutations, at positions R1275 and F1174, were observed (49% and 34.7% of the mutated cases, respectively). Interestingly, the F1174 mutations occurred in a high proportion of MYCN-amplified cases (P = 0.001), and this combined occurrence was associated with a particular poor outcome, suggesting a positive cooperative effect between both aberrations. Furthermore, the F1174L mutant was characterized by a higher degree of autophosphorylation and a more potent transforming capacity as compared with the R1275Q mutant. Chromosome 2p gains, including the ALK locus (91.8%), were associated with a significantly increased ALK expression, which was also correlated with poor survival. CONCLUSIONS:ALK mutations occur in equal frequencies across all genomic subtypes, but F1174L mutants are observed in a higher frequency of MYCN-amplified tumors and show increased transforming capacity as compared with the R1275Q mutants.
Authors: Scott C Bresler; Andrew C Wood; Elizabeth A Haglund; Joshua Courtright; Lili T Belcastro; Jefferson S Plegaria; Kristina Cole; Yana Toporovskaya; Huaqing Zhao; Erica L Carpenter; James G Christensen; John M Maris; Mark A Lemmon; Yaël P Mossé Journal: Sci Transl Med Date: 2011-11-09 Impact factor: 17.956
Authors: E L Carpenter; E A Haglund; E M Mace; D Deng; D Martinez; A C Wood; A K Chow; D A Weiser; L T Belcastro; C Winter; S C Bresler; M Vigny; P Mazot; S Asgharzadeh; R C Seeger; H Zhao; R Guo; J G Christensen; J S Orange; B R Pawel; M A Lemmon; Y P Mossé Journal: Oncogene Date: 2012-01-23 Impact factor: 9.867
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Authors: Shana Claeys; Geertrui Denecker; Kaat Durinck; Bieke Decaesteker; Liselot M Mus; Siebe Loontiens; Suzanne Vanhauwaert; Kristina Althoff; Caroline Wigerup; Daniel Bexell; Emmy Dolman; Kai-Oliver Henrich; Lea Wehrmann; Ellen M Westerhout; Jean-Baptiste Demoulin; Candy Kumps; Tom Van Maerken; Genevieve Laureys; Christophe Van Neste; Bram De Wilde; Olivier De Wever; Frank Westermann; Rogier Versteeg; Jan J Molenaar; Sven Påhlman; Johannes H Schulte; Katleen De Preter; Frank Speleman Journal: Oncogene Date: 2018-12-11 Impact factor: 9.867