Emergence of New ALK Mutations at Relapse of Neuroblastoma
2014 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 25, 2727-+ p.Article in journal (Refereed) Published
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. Methods 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%. Results 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%). Conclusion 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.
Place, publisher, year, edition, pages
American Society of Clinical Oncology: JCO , 2014. Vol. 32, no 25, 2727-+ p.
IdentifiersURN: urn:nbn:se:liu:diva-111275DOI: 10.1200/JCO.2013.54.0674ISI: 000341562600011PubMedID: 25071110OAI: oai:DiVA.org:liu-111275DiVA: diva2:755420
Funding Agencies|Annenberg Foundation; Site de Recherche Integre en Cancerologie/Institut National du Cancer [INCa-DGOS-4654]; Comite devaluation et suivi des projets de Recherche de Transfert of Institut Curie; Associations Enfants et Sante; Association Hubert Gouin Enfance et Cancer; Les Bagouz a Manon; Les Amis de Claire; EQUIPEX Investissements dAvenir program [ANR-10-EQPX-03]; Agence Nationale de le Recherche [ANR10-INBS-09-08]; Canceropole Ile-de-France; Swedish Cancer Society [12-817 TM]; Swedish Childrens Cancer Foundation [10-129 TM]; Swedish state through the LUA/ALF; BioCARE, a National Strategic Research Program at the University of Gothenburg; Fund for Scientific Research [G.0198.08, 31511809]; European Network for Cancer Research in Children and Adolescents: Seventh European Union Framework Programme [261474, 259348]; National Cancer Plan [KPC_29_010]2014-10-142014-10-142015-03-30