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

Adolescent Antineoplastic Combined Chemotherapy Protocols / pharmacology Biopsy Child Child, Preschool Clinical Decision-Making / methods Clinical Trials, Phase III as Topic Clonal Evolution DNA Copy Number Variations Drug Resistance, Neoplasm / genetics Female Gene Expression Profiling Genetic Heterogeneity Genomics Humans Infant Male Mutation Neoadjuvant Therapy / methods Neuroblastoma / diagnosis Randomized Controlled Trials as Topic Risk Assessment / methods Spatio-Temporal Analysis

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
23 11 2021
Historique:
received: 23 11 2020
accepted: 18 10 2021
entrez: 24 11 2021
pubmed: 25 11 2021
medline: 22 12 2021
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-021-26870-z PMID: 34815394 PMC: PMC8611017
pubmed: 34815394
doi: 10.1038/s41467-021-26870-z
pii: 10.1038/s41467-021-26870-z
pmc: PMC8611017
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

6804

Informations de copyright

© 2021. The Author(s).

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Auteurs

Karin Schmelz (K)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
The German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.
The German Cancer Research Center (DKFZ), Heidelberg, Germany.

Joern Toedling (J)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
The German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.
The German Cancer Research Center (DKFZ), Heidelberg, Germany.
ORCID: 0000-0003-1471-1295

Matt Huska (M)

Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
ORCID: 0000-0002-0912-745X

Maja C Cwikla (MC)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
ORCID: 0000-0002-6679-5577

Louisa-Marie Kruetzfeldt (LM)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
ORCID: 0000-0003-3630-3727

Jutta Proba (J)

Charité-Universitätsmedizin Berlin, Berlin, Germany.

Peter F Ambros (PF)

Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, 1090, Vienna, Austria.

Inge M Ambros (IM)

Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, 1090, Vienna, Austria.

Sengül Boral (S)

Charité-Universitätsmedizin Berlin, Berlin, Germany.

Marco Lodrini (M)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
The German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.
The German Cancer Research Center (DKFZ), Heidelberg, Germany.

Celine Y Chen (CY)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
Experimental and Clinical Research Center (ECRC) of the Charité and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
ORCID: 0000-0002-1579-024X

Martin Burkert (M)

Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.

Dennis Guergen (D)

Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Berlin, Germany.

Annabell Szymansky (A)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
ORCID: 0000-0003-4797-4526

Kathy Astrahantseff (K)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
ORCID: 0000-0002-7872-1997

Annette Kuenkele (A)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
The German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.
The German Cancer Research Center (DKFZ), Heidelberg, Germany.
Berlin Institute of Health (BIH), Berlin, Germany.

Kerstin Haase (K)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
The German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.
The German Cancer Research Center (DKFZ), Heidelberg, Germany.
Berlin Institute of Health (BIH), Berlin, Germany.
ORCID: 0000-0002-0944-5618

Matthias Fischer (M)

Department of Experimental Pediatric Oncology, Medical Faculty, University Children's Hospital of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
ORCID: 0000-0003-1363-1242

Hedwig E Deubzer (HE)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
The German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.
The German Cancer Research Center (DKFZ), Heidelberg, Germany.
Experimental and Clinical Research Center (ECRC) of the Charité and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Berlin Institute of Health (BIH), Berlin, Germany.
ORCID: 0000-0002-6115-4893

Falk Hertwig (F)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
The German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.
The German Cancer Research Center (DKFZ), Heidelberg, Germany.
ORCID: 0000-0003-4784-6516

Patrick Hundsdoerfer (P)

Charité-Universitätsmedizin Berlin, Berlin, Germany.
Helios Klinikum Berlin-Buch, Berlin, Germany.

Anton G Henssen (AG)

Charité-Universitätsmedizin Berlin, Berlin, Germany. anton.henssen@charite.de.
The German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany. anton.henssen@charite.de.
The German Cancer Research Center (DKFZ), Heidelberg, Germany. anton.henssen@charite.de.
Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. anton.henssen@charite.de.
Experimental and Clinical Research Center (ECRC) of the Charité and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. anton.henssen@charite.de.
Berlin Institute of Health (BIH), Berlin, Germany. anton.henssen@charite.de.
ORCID: 0000-0003-1534-778X

Roland F Schwarz (RF)

Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. roland.schwarz@mdc-berlin.de.
BIFOLD-Berlin Institute for the Foundations of Learning and Data, Berlin, Germany. roland.schwarz@mdc-berlin.de.
ORCID: 0000-0001-9155-4268

Johannes H Schulte (JH)

Charité-Universitätsmedizin Berlin, Berlin, Germany. johannes.schulte@charite.de.
The German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany. johannes.schulte@charite.de.
The German Cancer Research Center (DKFZ), Heidelberg, Germany. johannes.schulte@charite.de.
Berlin Institute of Health (BIH), Berlin, Germany. johannes.schulte@charite.de.
ORCID: 0000-0003-0671-1201

Angelika Eggert (A)

Charité-Universitätsmedizin Berlin, Berlin, Germany. angelika.eggert@charite.de.
The German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany. angelika.eggert@charite.de.
The German Cancer Research Center (DKFZ), Heidelberg, Germany. angelika.eggert@charite.de.
Berlin Institute of Health (BIH), Berlin, Germany. angelika.eggert@charite.de.
ORCID: 0000-0003-3476-8184

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Association de médicaments › Protocoles de polychimiothérapie antinéoplasique › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Techniques d'investigation › Techniques cytologiques › Cytodiagnostic › Biopsie › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Enfant d'âge préscolaire › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Diagnostic › Prise de décision clinique › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études cliniques comme sujet › Essais cliniques comme sujet › Essais cliniques de phase III comme sujet › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Phénomènes génétiques › Évolution clonale › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Variation structurale du génome › Variations de nombre de copies de segment d'ADN › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de profil d'expression de gènes › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Hétérogénéité génétique › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Spatial and temporal intratumour heterogeneity...
questionsmedicales.fr › Personnes › Tranches d'âge › Nourrisson › Spatial and temporal intratumour heterogeneity...
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questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse spatiale › Analyse spatio-temporelle › Spatial and temporal intratumour heterogeneity...