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Mutational topography reflects clinical neuroblastoma heterogeneity

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Item Type:Article
Title:Mutational topography reflects clinical neuroblastoma heterogeneity
Creators Name:Rodriguez-Fos, E. and Planas-Fèlix, M. and Burkert, M. and Puiggròs, M. and Toedling, J. and Thiessen, N. and Blanc, E. and Szymansky, A. and Hertwig, F. and Ishaque, N. and Beule, D. and Torrents, D. and Eggert, A. and Koche, R.P. and Schwarz, R.F. and Haase, K. and Schulte, J.H. and Henssen, A.G.
Abstract:Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although clinical risk-defining genomic alterations exist in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography and mutational signatures derived from all variant classes, we identified co-occurring mutational footprints, which we termed mutational scenarios. We demonstrate that clinical neuroblastoma heterogeneity is associated with differences in the mutational processes driving these scenarios, linking risk-defining pathognomonic variants to distinct molecular processes. Whereas high-risk MYCN-amplified neuroblastomas were characterized by signs of replication slippage and stress, homologous recombination-associated signatures defined high-risk non-MYCN-amplified patients. Non-high-risk neuroblastomas were marked by footprints of chromosome mis-segregation and TOP1 mutational activity. Furthermore, analysis of subclonal mutations uncovered differential activity of these processes through neuroblastoma evolution. Thus, clinical heterogeneity of neuroblastoma patients can be linked to differences in the mutational processes that are active in their tumors.
Keywords:Neuroblastoma, Mutational Signatures, Cancer Genomics, Tumor Evolution, ecDNA, Complex Rearrangements, Structural Variation, Clinical Heterogeneity, Mutational Processes
Source:Cell Genomics
Publisher:Cell Press
Page Range:100402
Date:11 October 2023
Official Publication:https://doi.org/10.1016/j.xgen.2023.100402
PubMed:View item in PubMed

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