TY - JOUR
T1 - Meta-analysis of Neuroblastomas Reveals a Skewed ALK Mutation Spectrum in Tumors with MYCN Amplification
AU - de Brouwer, Sara
AU - de Preter, Katleen
AU - Kumps, Candy
AU - Zabrocki, Piotr
AU - Porcu, Michaël
AU - Westerhout, Ellen M.
AU - Lakeman, Arjan
AU - Vandesompele, Jo
AU - Hoebeeck, Jasmien
AU - van Maerken, Tom
AU - de Paepe, Anne
AU - Laureys, Geneviève
AU - Schulte, Johannes H.
AU - Schramm, Alexander
AU - van den Broecke, Caroline
AU - Vermeulen, Joëlle
AU - van Roy, Nadine
AU - Beiske, Klaus
AU - Renard, Marleen
AU - Noguera, Rosa
AU - Delattre, Olivier
AU - Janoueix-Lerosey, Isabelle
AU - Kogner, Per
AU - Martinsson, Tommy
AU - Nakagawara, Akira
AU - Ohira, Miki
AU - Caron, Huib N.
AU - Eggert, Angelika
AU - Cools, Jan
AU - Versteeg, Rogier
AU - Speleman, Frank
PY - 2010
Y1 - 2010
N2 - 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. Clin Cancer Res; 16(17); 4353-62. (C) 2010 AACR
AB - 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. Clin Cancer Res; 16(17); 4353-62. (C) 2010 AACR
U2 - https://doi.org/10.1158/1078-0432.CCR-09-2660
DO - https://doi.org/10.1158/1078-0432.CCR-09-2660
M3 - Article
C2 - 20719933
SN - 1078-0432
VL - 16
SP - 4353
EP - 4362
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -