Meta-analysis of Neuroblastomas Reveals a Skewed ALK Mutation Spectrum in Tumors with MYCN Amplification.

Meta-analysis of Neuroblastomas Reveals a Skewed ALK Mutation Spectrum in Tumors with MYCN Amplification.

Clin Cancer Res. 2010 Aug 18;

Authors: De Brouwer S, De Preter K, Kumps C, Zabrocki P, Porcu M, Westerhout EM, Lakeman A, Vandesompele J, Hoebeeck J, Van Maerken T, De Paepe A, Laureys G, Schulte JH, Schramm A, Van Den Broecke C, Vermeulen J, Van Roy N, Beiske K, Renard M, Noguera R, Delattre O, Janoueix-Lerosey I, Kogner P, Martinsson T, Nakagawara A, Ohira M, Caron HN, Eggert A, Cools J, Versteeg R, Speleman F

PURPOSE: Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We performed a meta-analysis of 709 neuroblastoma tumors to determine its frequency and mutation spectrum in relation to genomic and clinical parameters and studied the prognostic significance of ALK copy number and expression.EXPERIMENTAL DESIGN: 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 (INSS 1, 2 and 4S; 5.7%) and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P=.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=.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 auto-phosphorylation and a more potent transforming capacity as compared to 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 to the R1275Q mutants.

PMID: 20719933 [PubMed - as supplied by publisher]

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Posted 20 Aug 2010 3:29 AM by pubmed: neuroblastoma
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