Schmelz, Karin, Toedling, Joern, Huska, Matt, Cwikla, Maja C., Kruetzfeldt, Louisa-Marie, Proba, Jutta, Ambros, Peter F., Ambros, Inge M., Boral, Sengul, Lodrini, Marco, Chen, Celine Y., Burkert, Martin ORCID: 0000-0002-6721-9985, 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. and Eggert, Angelika ORCID: 0000-0003-3476-8184 (2021). Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions. Nat. Commun., 12 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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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. 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schmelz, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toedling, JoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huska, MattUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cwikla, Maja C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kruetzfeldt, Louisa-MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Proba, JuttaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ambros, Peter F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ambros, Inge M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boral, SengulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lodrini, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, Celine Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burkert, MartinUNSPECIFIEDorcid.org/0000-0002-6721-9985UNSPECIFIED
Guergen, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szymansky, AnnabellUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Astrahantseff, KathyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuenkele, AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haase, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deubzer, Hedwig E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hertwig, FalkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hundsdoerfer, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henssen, Anton G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarz, Roland F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, Johannes H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eggert, AngelikaUNSPECIFIEDorcid.org/0000-0003-3476-8184UNSPECIFIED
URN: urn:nbn:de:hbz:38-600465
DOI: 10.1038/s41467-021-26870-z
Journal or Publication Title: Nat. Commun.
Volume: 12
Number: 1
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACTIVATING MUTATIONS; TARGETED THERAPY; RISK; LANDSCAPE; SURVIVAL; CLASSIFICATION; GENOMEMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60046

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