%0 Journal Article
%A Rodriguez-Fos, Elias
%A Planas-Fèlix, Mercè
%A Burkert, Martin
%A Puiggròs, Montserrat
%A Toedling, Joern
%A Thiessen, Nina
%A Blanc, Eric
%A Szymansky, Annabell
%A Hertwig, Falk
%A Ishaque, Naveed
%A Beule, Dieter
%A Torrents, David
%A Eggert, Angelika
%A Koche, Richard P.
%A Schwarz, Roland F.
%A Haase, Kerstin
%A Schulte, Johannes H.
%A Henssen, Anton G.
%T Mutational topography reflects clinical neuroblastoma heterogeneity
%J Cell genomics
%V 3
%N 10
%@ 2666-979X
%C Amsterdam
%I Elsevier
%M DKFZ-2023-02084
%P 100402
%D 2023
%X Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although clinicalrisk-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 variantclasses, we identified co-occurring mutational footprints, which we termed mutational scenarios. We demonstrate that clinical neuroblastoma heterogeneity is associated with differences in the mutational processesdriving these scenarios, linking risk-defining pathognomonic variants to distinct molecular processes.Whereas high-risk MYCN-amplified neuroblastomas were characterized by signs of replication slippageand stress, homologous recombination-associated signatures defined high-risk non-MYCN-amplified patients. Non-high-risk neuroblastomas were marked by footprints of chromosome mis-segregation andTOP1 mutational activity. Furthermore, analysis of subclonal mutations uncovered differential activity ofthese processes through neuroblastoma evolution. Thus, clinical heterogeneity of neuroblastoma patientscan be linked to differences in the mutational processes that are active in their tumors.
%F PUB:(DE-HGF)16
%9 Journal Article
%R 10.1016/j.xgen.2023.100402
%U https://inrepo02.dkfz.de/record/284773