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Emergence of New ALK Mutations at Relapse of Neuroblastoma

Journal article
Authors G. Schleiermacher
Niloufar Javanmardi
V. Bernard
Q. Leroy
J. Cappo
T. R. Frio
G. Pierron
E. Lapouble
V. Combaret
F. Speleman
B. de Wilde
Anna Djos
I. Ora
F. Hedborg
C. Trager
B. M. Holmqvist
Jonas Abrahamsson
M. Peuchmaur
J. Michon
I. Janoueix-Lerosey
P. Kogner
O. Delattre
Tommy Martinsson
Published in Journal of Clinical Oncology
Volume 32
Issue 25
Pages 2727-2734
ISSN 0732-183X
Publication year 2014
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Institute of Clinical Sciences, Department of Pediatrics
Pages 2727-2734
Language en
Subject categories Cancer and Oncology, Clinical Medicine


Purpose In neuroblastoma, the ALK receptor tyrosine kinase is activated by point mutations. We investigated the potential role of ALK mutations in neuroblastoma clonal evolution. We analyzed ALK mutations in 54 paired diagnosis-relapse neuroblastoma samples using Sanger sequencing. When an ALK mutation was observed in one paired sample, a minor mutated component in the other sample was searched for by more than 100,000 x deep sequencing of the relevant hotspot, with a sensitivity of 0.17%. All nine ALK-mutated cases at diagnosis demonstrated the same mutation at relapse, in one case in only one of several relapse nodules. In five additional cases, the mutation seemed to be relapse specific, four of which were investigated by deep sequencing. In two cases, no mutation evidence was observed at diagnosis. In one case, the mutation was present at a subclonal level (0.798%) at diagnosis, whereas in another case, two different mutations resulting in identical amino acid changes were detected, one only at diagnosis and the other only at relapse. Further evidence of clonal evolution of ALK-mutated cells was provided by establishment of a fully ALK-mutated cell line from a primary sample with an ALK-mutated cell population at subclonal level (6.6%). In neuroblastoma, subclonal ALK mutations can be present at diagnosis with subsequent clonal expansion at relapse. Given the potential of ALK-targeted therapy, the significant spatiotemporal variation of ALK mutations is of utmost importance, highlighting the potential of deep sequencing for detection of subclonal mutations with a sensitivity 100-fold that of Sanger sequencing and the importance of serial samplings for therapeutic decisions.

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