Journal
BRITISH JOURNAL OF CANCER
Volume 118, Issue 11, Pages 1502-1512Publisher
SPRINGERNATURE
DOI: 10.1038/s41416-018-0098-6
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Funding
- FIS [PI14/01008]
- Institute of Health Carlos III [RD12/36/20, CB16/12/00484]
- ERDF [RD12/36/20, CB16/12/00484]
- FAECC
- Austrian Science Fund (FWF) [I 2799-B28]
- European Union's Seventh Framework Program (FP7/2007-2013) under the project ENCCA [HEALTH-F2-2011-261474]
- Italian Neuroblastoma Foundation
- Austrian Science Fund (FWF) [I2799] Funding Source: Austrian Science Fund (FWF)
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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.
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