Journal Article

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

Ambros, Inge M., Guergen, Dennis, Hundsdoerfer, Patrick, Kuenkele, Annette, Schmelz, Karin, Huska, Matt, Henssen, Anton G., Eggert, Angelika, Lodrini, Marco, Szymansky, Annabell, Ambros, Peter F., Cwikla, Maja C., Boral, Sengül, Chen, Celine Y., Schulte, Johannes H., Haase, Kerstin, Burkert, Martin, Kruetzfeldt, Louisa-Marie, Hertwig, Falk, Fischer, Matthias, Schwarz, Roland F., Astrahantseff, Kathy, Toedling, Joern, Proba, Jutta, Deubzer, Hedwig E.

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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