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

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. Clin Cancer Res; 16(17); 4353-62. ©2010 AACR.

VIP and PACAP analogs regulate therapeutic targets in high-risk neuroblastoma cells

“…Numerous ALK mutations have been identified in NB cells [9]. The ALK mutations F1178L and R1279Q were recently shown to increase VIP expression in NB tumors from mice with one of these ALK mutations and overexpressing MYCN [46].…”

“…This tyrosine kinase receptor collaborates with MYCN for the development of most aggressive NB [8]. The F1174L ALK mutation is associated preferentially with MYCN amplification in NB and induces constitutive activation of the PI3K/AKT pathway [9,10]. This constitutive activation leads to oncogenic stabilization of MYCN protein [11].…”

“…This constitutive activation leads to oncogenic stabilization of MYCN protein [11]. Poorly differentiated NB with high expression of MYCN and the F1174L ALK mutation define a subset of patients with high-risk NB [9,12].…”

Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells

“…1,2 Genetically, many cases of neuroblastoma show amplification of the MYCN gene (B24% of all cases), deletions of parts of the chromosomes 1p and 11q, gain of parts of 17q and triploidy. 1,3 --6 Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase (RTK) is mutated in both familial and somatic neuroblastoma.…”

Exposure of neuroblastoma cell lines to imatinib results in the upregulation of the CDK inhibitor p27KIP1 as a consequence of c-Abl inhibition

“…IMR5, SK-N-AS, and SK-N-F1 cells have the wild-type and unamplified ALK gene [18,19]. IMR5 and SK-N-F1 are of N-type [20,21], SK-N-AS cells are of S-type [22].…”