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Title: Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification
Authors: De Brouwer, Sara ×
De Preter, Katleen
Kumps, Candy
Zabrocki, Piotr
Porcu, Michaƫl
Westerhout, Ellen M
Lakeman, Arjan
Vandesompele, Jo
Hoebeeck, Jasmien
Van Maerken, Tom
De Paepe, Anne
Laureys, Geneviève
Schulte, Johannes H
Schramm, Alexander
Van Den Broecke, Caroline
Vermeulen, Joëlle
Van Roy, Nadine
Beiske, Klaus
Renard, Marleen
Noguera, Rosa
Delattre, Olivier
Janoueix-Lerosey, Isabelle
Kogner, Per
Martinsson, Tommy
Nakagawara, Akira
Ohira, Miki
Caron, Huib
Eggert, Angelika
Cools, Jan
Versteeg, Rogier
Speleman, Frank #
Issue Date: 1-Sep-2010
Publisher: Association for Cancer Research
Series Title: Clinical Cancer Research vol:16 issue:17 pages:4353-4362
Abstract: 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.
URI: 
ISSN: 1078-0432
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Molecular Biology of Leukemia
Section Child - Miscellaneous (-)
× corresponding author
# (joint) last author

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