Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification

G Schleiermacher, J Michon, I Huon, C Dubois d'Enghien, J Klijanienko, H Brisse, A Ribeiro, V Mosseri, H Rubie, C Munzer, C Thomas, D Valteau-Couanet, A Auvrignon, D Plantaz, O Delattre, J Couturier, Société Française des Cancers de l'Enfant (SFCE), G Schleiermacher, J Michon, I Huon, C Dubois d'Enghien, J Klijanienko, H Brisse, A Ribeiro, V Mosseri, H Rubie, C Munzer, C Thomas, D Valteau-Couanet, A Auvrignon, D Plantaz, O Delattre, J Couturier, Société Française des Cancers de l'Enfant (SFCE)

Abstract

Whereas neuroblastoma (NB) with MYCN amplification presents a poor prognosis, no single marker allows to reliably predict outcome in tumours without MYCN amplification. We report here an extensive analysis of 147 NB samples at diagnosis, without MYCN amplification, by chromosomal comparative genomic hybridisation (CGH), providing a comprehensive overview of their genomic imbalances. Comparative genomic hybridisation profiles showed gains or losses of entire chromosomes (type 1) in 71 cases, whereas partial chromosome gains or losses (type 2), including gain involving 17q were observed in 68 cases. Atypical profiles were present in eight cases. A type 1 profile was observed more frequently in localised disease (P<0.0001), and in patients of less than 12 months at diagnosis (P<0.0001). A type 2 genomic profile was associated with a higher risk of relapse in the overall population (log-rank test; P<0.0001), but also in the subgroup of patients with localised disease (log-rank test, P=0.007). In multivariate analysis, the genomic profile was the strongest independent prognostic factor. In conclusion, the genomic profile is of prognostic impact in patients without MYCN amplification, making it a help in the management of low-stage NB. Further studies using higher-resolution CGH are needed to better characterise atypical genomic alterations.

Figures

Figure 1
Figure 1
Diagram showing gains and losses detected by chromosomal CGH in tumours with a type 1 genomic profile, characterised by numerical chromosome alterations. Losses are indicated by a bar on the left and gains by a bar on the right of each chromosome ideogram. Each bar represents an alteration observed in one tumour.
Figure 2
Figure 2
Diagram showing gains and losses detected by chromosomal CGH in tumours with a type 2 genomic profile, characterised by segmental chromosome alterations. Losses are indicated by a bar on the left and gains by a bar on the right of each chromosome ideogram. Each bar represents an alteration observed in one tumour. (A) Segmental alterations observed in tumours without chromosome 1p deletions (type 2a). (B) Segmental alterations observed in tumours with chromosome 1p deletions (type 2b).
Figure 3
Figure 3
Survival curves of 139 neuroblastoma patients. (A) Event-free survival of all patients. (B) Overall survival of all patients. (C) Event-free survival according to stage at diagnosis. (D) Event-free survival according to age at diagnosis.
Figure 4
Figure 4
Survival curves according to genetic markers. (A) Event-free survival according to chromosome 11q status. (B) Event-free survival according to chromosome 17q status. (C) Event-free survival according to the genomic profile, type 1 referring to numerical alterations, and type 2a and 2b referring to structural chromosome alterations without or with chromosome 1p loss. (D) Metastasis-free survival according to the genomic profile.

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