Heterogeneous MYCN amplification in neuroblastoma: A SIOP Europe Neuroblastoma Study

Ana P. Berbegall, Dominik Bogen, Ulrike Pötschger, Klaus Beiske, Nick Bown, Valérie Combaret, Raffaella Defferrari, Marta Jeison, Katia Mazzocco, Luigi Varesio, Ales Vicha, Shifra Ash, Victoria Castel, Carole Coze, Ruth Ladenstein, Cormac Owens, Vassilios Papadakis, Ellen Ruud, Gabriele Amann, Angela R. SementaSamuel Navarro, Peter F. Ambros, Rosa Noguera, Inge M. Ambros

Research output: Contribution to journalArticle

Abstract

Background: In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues. Methods: The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH. Results: Patients <18 months (18 m) showed a better outcome in all stages as compared to older patients (5-year OS in localised stages: <18 m: 0.95 ± 0.04, >18 m: 0.67 ± 0.14, p = 0.011; metastatic: <18 m: 0.76 ± 0.15, >18 m: 0.28 ± 0.09, p = 0.084). The genomic 'background', but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse. Conclusions: This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA.

Original languageEnglish
Pages (from-to)1502-1512
Number of pages11
JournalBritish Journal of Cancer
Volume118
Issue number11
DOIs
Publication statusPublished - May 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Berbegall, A. P., Bogen, D., Pötschger, U., Beiske, K., Bown, N., Combaret, V., Defferrari, R., Jeison, M., Mazzocco, K., Varesio, L., Vicha, A., Ash, S., Castel, V., Coze, C., Ladenstein, R., Owens, C., Papadakis, V., Ruud, E., Amann, G., ... Ambros, I. M. (2018). Heterogeneous MYCN amplification in neuroblastoma: A SIOP Europe Neuroblastoma Study. British Journal of Cancer, 118(11), 1502-1512. https://doi.org/10.1038/s41416-018-0098-6