1. Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions.
- Author
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Schmelz K, Toedling J, Huska M, Cwikla MC, Kruetzfeldt LM, Proba J, Ambros PF, Ambros IM, Boral S, Lodrini M, Chen CY, Burkert M, Guergen D, Szymansky A, Astrahantseff K, Kuenkele A, Haase K, Fischer M, Deubzer HE, Hertwig F, Hundsdoerfer P, Henssen AG, Schwarz RF, Schulte JH, and Eggert A
- Subjects
- Adolescent, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biopsy, Child, Child, Preschool, Clinical Trials, Phase III as Topic, Clonal Evolution, DNA Copy Number Variations, Drug Resistance, Neoplasm genetics, Female, Gene Expression Profiling, Genomics, Humans, Infant, Male, Mutation, Neoadjuvant Therapy statistics & numerical data, Neuroblastoma diagnosis, Neuroblastoma genetics, Neuroblastoma pathology, Randomized Controlled Trials as Topic, Risk Assessment methods, Spatio-Temporal Analysis, Antineoplastic Combined Chemotherapy Protocols pharmacology, Clinical Decision-Making methods, Genetic Heterogeneity, Neoadjuvant Therapy methods, Neuroblastoma therapy
- 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., (© 2021. The Author(s).)
- Published
- 2021
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