Distinct evolutionary mechanisms for genomic imbalances in high-risk and low-risk neuroblastomas

David Gisselsson¹^,2 , Gisela Lundberg¹ , Ingrid Øra³ and Mattias Höglund¹

¹Department of Clinical Genetics, Lund University Hospital, SE 221 85 Lund, Sweden

²Department of Pathology, Lund University Hospital, SE 221 85 Lund, Sweden

³Department of Paediatric Haematology and Oncology, Lund University Hospital, SE 221 85 Lund, Sweden

author email corresponding author email

Journal of Carcinogenesis 2007, 6:15doi:10.1186/1477-3163-6-15


Published:	26 September 2007

Abstract

Background

Neuroblastoma (NB) is the most common extracranial solid tumour of childhood. Several genomic imbalances correlate to prognosis in NB, with structural rearrangements, including gene amplification, in a near-diploid setting typically signifying high-risk tumours and numerical changes in a near-triploid setting signifying low-risk tumours. Little is known about the temporal sequence in which these imbalances occur during the carcinogenic process.

Methods

We have reconstructed the appearance of cytogenetic imbalances in 270 NBs by first grouping tumours and imbalances through principal component analysis and then using the number of imbalances in each tumour as an indicator of evolutionary progression.

Results

Tumours clustered in four sub-groups, dominated respectively by (1) gene amplification in double minute chromosomes and few other aberrations, (2) gene amplification and loss of 1p sequences, (3) loss of 1p and other structural aberrations including gain of 17q, and (4) whole-chromosome gains and losses. Temporal analysis showed that the structural changes in groups 1–3 were acquired in a step-wise fashion, with loss of 1p sequences and the emergence of double minute chromosomes as the earliest cytogenetic events. In contrast, the gains and losses of whole chromosomes in group 4 occurred through multiple simultaneous events leading to a near-triploid chromosome number.

Conclusion

The finding of different temporal patterns for the acquisition of genomic imbalances in high-risk and low-risk NBs lends strong support to the hypothesis that these tumours are biologically diverse entities, evolving through distinct genetic mechanisms.