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 Sementa, Samuel Navarro, Peter F Ambros, Rosa Noguera, Inge M Ambros, 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 Sementa, Samuel Navarro, Peter F Ambros, Rosa Noguera, Inge M Ambros

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.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Oncoplot summarising clinical and genetic data. All hetMNA tumours for the two age groups, below (a) and above (b) 18 months of age, are shown separately and arranged according to the absence or presence of segmental chromosome aberrations, indicating also ploidy, MNA clone sizes in the analysed samples and clinical data: INSS stage, treatment, the presence of relapse or progressions, and outcome. In case of no events, observation times are at least 3 years, with the exception for two patients which are indicated. NCA numerical chromosome aberrations, het typSCA heterogeneous typical segmental aberrations, atypSCA atypical segmental aberrations, typSCA typical segmental aberrations, ne not evaluable, nd no data, MNAMYCN amplification, INSS International Neuroblastoma Staging System, CTX cytotoxic therapy, D dead, not disease-related, DOD dead of disease, DOT dead of therapy. Note: MNA clone size categories: 1: <1; 2: 1–5; 3: 6–10; 4: 11–50; 5: >50%
Fig. 2
Fig. 2
Kaplan–Meier event-free survival curves by INSS stages, age and genomic status. Sixty-month event-free survivals (EFS) for stage (any stage, localised stages and metastatic stages) according to age (first row) and cumulative incidence of relapses (CIRs) (second row); 60-month EFS according to the genomic background (third row; left: according to presence or absence of numerical and typical segmental chromosome aberrations, NCA, SCA; right: according to ploidy); CIR according to genomic background, any age (fourth row); CIR according to NCA/SCA in the two age groups (fifth row); CIR according to ploidy in the two age groups (sixth row). pts patients, rel relapse; m months
Fig. 2
Fig. 2
Kaplan–Meier event-free survival curves by INSS stages, age and genomic status. Sixty-month event-free survivals (EFS) for stage (any stage, localised stages and metastatic stages) according to age (first row) and cumulative incidence of relapses (CIRs) (second row); 60-month EFS according to the genomic background (third row; left: according to presence or absence of numerical and typical segmental chromosome aberrations, NCA, SCA; right: according to ploidy); CIR according to genomic background, any age (fourth row); CIR according to NCA/SCA in the two age groups (fifth row); CIR according to ploidy in the two age groups (sixth row). pts patients, rel relapse; m months

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