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.

• Authors: Sara De Brouwer, Katleen De Preter, Candy Kumps, Piotr Zabrocki, Michaël Porcu, Ellen M Westerhout, Arjan Lakeman, Jo Vandesompele, Jasmien Hoebeeck, Tom Van Maerken, Anne De Paepe, Geneviève Laureys, Johannes H Schulte, Alexander Schramm, Caroline Van Den Broecke, Joëlle Vermeulen, Nadine Van Roy, Klaus Beiske, Marleen Renard, Rosa Noguera, Olivier Delattre, Isabelle Janoueix-Lerosey, Per Kogner, Tommy Martinsson, Akira Nakagawara, Miki Ohira, Huib Caron, Angelika Eggert, Jan Cools, Rogier Versteeg, Frank Speleman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 17 Pg. 4353-62 (Sep 01 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20719933 (Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't)

Chemical References

• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Nuclear Proteins
• Oncogene Proteins
• ALK protein, human
• Anaplastic Lymphoma Kinase
• Protein-Tyrosine Kinases
• Receptor Protein-Tyrosine Kinases

Topics

• Amino Acid Substitution
• Anaplastic Lymphoma Kinase
• Animals
• Cell Line, Transformed
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics)
• Gene Amplification
• Gene Expression Profiling
• Gene Frequency
• Humans
• Kaplan-Meier Estimate
• Mutation
• N-Myc Proto-Oncogene Protein
• Neuroblastoma (genetics, metabolism)
• Nuclear Proteins (genetics)
• Oncogene Proteins (genetics)
• Phosphorylation
• Protein-Tyrosine Kinases (genetics, metabolism)
• Receptor Protein-Tyrosine Kinases