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

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 spat...

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Bibliographic Details
Published in:	Nature communications Vol. 12; no. 1; p. 6804
Main Authors:	Schmelz, Karin, Toedling, Joern, Huska, Matt, Cwikla, Maja C., Kruetzfeldt, Louisa-Marie, Proba, Jutta, Ambros, Peter F., Ambros, Inge M., Boral, Sengül, Lodrini, Marco, Chen, Celine Y., Burkert, Martin, Guergen, Dennis, Szymansky, Annabell, Astrahantseff, Kathy, Kuenkele, Annette, Haase, Kerstin, Fischer, Matthias, Deubzer, Hedwig E., Hertwig, Falk, Hundsdoerfer, Patrick, Henssen, Anton G., Schwarz, Roland F., Schulte, Johannes H., Eggert, Angelika
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 23-11-2021 Nature Publishing Group Nature Portfolio
Subjects:	45 45/23 45/91 631/67/1922 631/67/2329 631/67/2332 631/67/68 631/67/69 Adolescent Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biopsy Child Child, Preschool Children Chromosome aberrations Clinical Decision-Making - methods Clinical Trials, Phase III as Topic Clonal Evolution Copy number Decisions DNA Copy Number Variations Drug Resistance, Neoplasm - genetics Evolution Failure analysis Female Fibroblast growth factor receptor 1 Gene Expression Profiling Genetic Heterogeneity Genomic instability Genomics Heterogeneity Humanities and Social Sciences Humans Infant Male Metastases multidisciplinary Mutation Neoadjuvant Therapy - methods Neoadjuvant Therapy - statistics & numerical data Neuroblastoma Neuroblastoma - diagnosis Neuroblastoma - genetics Neuroblastoma - pathology Neuroblastoma - therapy Patients Randomized Controlled Trials as Topic Risk Assessment - methods Science Science (multidisciplinary) Spatial heterogeneity Spatio-Temporal Analysis Therapy Transcriptomics Tumors
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Summary:	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. Neuroblastoma is a devastating tumour in children. Here, the authors analyse multi-region patient samples using genomics and transcriptomics, revealing temporal and spatial heterogeneity and questioning the reliability of single-biopsy based diagnostics.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-26870-z