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Integrated genomic profiling identifies two distinct molecular subtypes with divergent outcome in neuroblastoma with loss of chromosome 11q

Abstract

Imbalances in chromosome 11q occur in approximately 30% of primary neuroblastoma and are associated with poor outcome. It has been suggested that 11q loss constitutes a distinct clinico-genetic neuroblastoma subgroup by affecting expression levels of corresponding genes. This study analysed the relationship of 11q loss, clinical phenotype and global transcriptomic profiles in four clinico-genetic subgroups (11q alteration/favourable outcome, n=7; 11q alteration/unfavourable outcome, n=14; no 11q alteration/favourable outcome, n=81; no 11q alteration/unfavourable outcome, n=8; tumours with MYCN amplification and/or 1p loss were excluded). Unsupervised and supervised comparisons of gene expression profiles consistently showed significantly different mRNA patterns between favourable and unfavourable neuroblastomas, both in the subgroups with and without 11q loss. In contrast, favourable tumours with and without 11q loss showed highly similar transcriptomic profiles. Disproportionate downregulation of 11q genes was observed only in unfavourable tumours with 11q loss. The diverging molecular profiles were neither caused by considerable differences in the size of the deleted regions nor by differential methylation patterns of 11q genes. Together, this study shows that neuroblastoma with 11q loss comprises two biological subgroups that differ both in their clinical phenotype and gene expression patterns, indicating that 11q loss is not a primary determinant of neuroblastoma tumour behaviour.

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Acknowledgements

We are grateful to Yvonne Kahlert for excellent technical assistance and to Dr Roman Thomas for critical reading of the paper. This work was supported by grants from the Deutsche Krebshilfe (Grant 50-2719), the Bundesministerium für Bildung und Forschung (BMBF) through the National Genome Research Network 2 (NGFN2, Grants 01GS0456 and 01GR0450) and the Competence Network Paediatric Oncology and Hematology (KPOH) as well as the Fördergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V.

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Correspondence to M Fischer.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Fischer, M., Bauer, T., Oberthür, A. et al. Integrated genomic profiling identifies two distinct molecular subtypes with divergent outcome in neuroblastoma with loss of chromosome 11q. Oncogene 29, 865–875 (2010). https://doi.org/10.1038/onc.2009.390

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