biostudies-literatureSchmelz KBundesministerium für Bildung und ForschungAustrian Science Fund FWFBerlin Institute of Health (TERMINATE-NB CRG04 collaborative research project) and in the TransTumVar project6804https://www.ebi.ac.uk/biostudies/studies/S-EPMC8611017biostudies-literatureUnknown12(1)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.Nature communicationsSpatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions.PMC8611017#01ZX1307#01ZX1607I 2799-B28Kuenkele ASchwarz RFAstrahantseff KGuergen DDeubzer HESchmelz KHuska MBurkert MSchulte JHToedling JCwikla MCChen CYHenssen AGEggert ALodrini MAmbros PFSzymansky AHundsdoerfer PKruetzfeldt LMHertwig FProba JHaase KAmbros IMFischer MBoral SfalseSpatial 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 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.2021-01-01T00:00:00Z2021 Nov2024-10-14T20:47:15.459Z2022-02-11T13:29:50.272ZS-EPMC86110173481539410.1038/s41467-021-26870-z