Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions

Karin Schmelz, Joern Toedling, Matt Huska, Maja C. Cwikla, Louisa-Marie Kruetzfeldt, Jutta Proba, Peter F. Ambros, Inge M. Ambros, Sengül Boral, Marco Lodrini, Celine Y. Chen, Martin Burkert, Dennis Guergen, Annabell Szymansky, Kathy Astrahantseff, Annette Kuenkele, Kerstin Haase, Matthias Fischer, Hedwig E. Deubzer, Falk Hertwig, Patrick Hundsdoerfer, Anton G. Henssen (), Roland F. Schwarz (), Johannes H. Schulte () and Angelika Eggert ()
Additional contact information
Karin Schmelz: Charité—Universitätsmedizin Berlin
Joern Toedling: Charité—Universitätsmedizin Berlin
Matt Huska: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Maja C. Cwikla: Charité—Universitätsmedizin Berlin
Louisa-Marie Kruetzfeldt: Charité—Universitätsmedizin Berlin
Jutta Proba: Charité—Universitätsmedizin Berlin
Peter F. Ambros: St. Anna Kinderkrebsforschung
Inge M. Ambros: St. Anna Kinderkrebsforschung
Sengül Boral: Charité—Universitätsmedizin Berlin
Marco Lodrini: Charité—Universitätsmedizin Berlin
Celine Y. Chen: Charité—Universitätsmedizin Berlin
Martin Burkert: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Dennis Guergen: Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO)
Annabell Szymansky: Charité—Universitätsmedizin Berlin
Kathy Astrahantseff: Charité—Universitätsmedizin Berlin
Annette Kuenkele: Charité—Universitätsmedizin Berlin
Kerstin Haase: Charité—Universitätsmedizin Berlin
Matthias Fischer: Department of Experimental Pediatric Oncology, Medical Faculty, University Children’s Hospital of Cologne
Hedwig E. Deubzer: Charité—Universitätsmedizin Berlin
Falk Hertwig: Charité—Universitätsmedizin Berlin
Patrick Hundsdoerfer: Charité—Universitätsmedizin Berlin
Anton G. Henssen: Charité—Universitätsmedizin Berlin
Roland F. Schwarz: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Johannes H. Schulte: Charité—Universitätsmedizin Berlin
Angelika Eggert: Charité—Universitätsmedizin Berlin

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Intratumour heterogeneity is a major cause of treatment failure in cancer. We present in-depth analyses combining transcriptomic and genomic profiling with ultra-deep targeted sequencing of multiregional biopsies in 10 patients with neuroblastoma, a devastating childhood tumour. We observe high spatial and temporal heterogeneity in somatic mutations and somatic copy-number alterations which are reflected on the transcriptomic level. Mutations in some druggable target genes including ALK and FGFR1 are heterogeneous at diagnosis and/or relapse, raising the issue whether current target prioritization and molecular risk stratification procedures in single biopsies are sufficiently reliable for therapy decisions. The genetic heterogeneity in gene mutations and chromosome aberrations observed in deep analyses from patient courses suggest clonal evolution before treatment and under treatment pressure, and support early emergence of metastatic clones and ongoing chromosomal instability during disease evolution. We report continuous clonal evolution on mutational and copy number levels in neuroblastoma, and detail its implications for therapy selection, risk stratification and therapy resistance.

Date: 2021
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DOI: 10.1038/s41467-021-26870-z

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