Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.
OBJECTIVE
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.


METHODS
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.
De Brouwer
Sara
S
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
De Preter
Katleen
K
Kumps
Candy
C
Zabrocki
Piotr
P
Porcu
Michaël
M
Westerhout
Ellen M
EM
Lakeman
Arjan
A
Vandesompele
Jo
J
Hoebeeck
Jasmien
J
Van Maerken
Tom
T
De Paepe
Anne
A
Laureys
Geneviève
G
Schulte
Johannes H
JH
Schramm
Alexander
A
Van Den Broecke
Caroline
C
Vermeulen
Joëlle
J
Van Roy
Nadine
N
Beiske
Klaus
K
Renard
Marleen
M
Noguera
Rosa
R
Delattre
Olivier
O
Janoueix-Lerosey
Isabelle
I
Kogner
Per
P
Martinsson
Tommy
T
Nakagawara
Akira
A
Ohira
Miki
M
Caron
Huib
H
Eggert
Angelika
A
Cools
Jan
J
Versteeg
Rogier
R
Speleman
Frank
F
D019943:Amino Acid Substitution; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005784:Gene Amplification; D020869:Gene Expression Profiling; D005787:Gene Frequency; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases