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Mutational dynamics between primary and relapse neuroblastomas

Item Type:Article
Title:Mutational dynamics between primary and relapse neuroblastomas
Creators Name:Schramm, A. and Köster, J. and Assenov, Y. and Althoff, K. and Peifer, M. and Mahlow, E. and Odersky, A. and Beisser, D. and Ernst, C. and Henssen, A.G. and Stephan, H. and Schröder, C. and Heukamp, L. and Engesser, A. and Kahlert, Y. and Theissen, J. and Hero, B. and Roels, F. and Altmüller, J. and Nürnberg, P. and Astrahantseff, K. and Gloeckner, C. and De Preter, K. and Plass, C. and Lee, S. and Lode, H.N. and Henrich, K.O. and Gartlgruber, M. and Speleman, F. and Schmezer, P. and Westermann, F. and Rahmann, S. and Fischer, M. and Eggert, A. and Schulte, J.H.
Abstract:Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.
Keywords:Comparative Genomic Hybridization, DNA Copy Number Variations, DNA Helicases, DNA Sequence Analysis, Exome, Fluorescence In Situ Hybridization, Gene Expression Profiling, Gene Frequency, Guanine Nucleotide Exchange Factors, Local Neoplasm Recurrence, Mutation, Neoplastic Gene Expression Regulation, Nerve Tissue Proteins, Neuroblastoma, Non-Receptor Protein Tyrosine Phosphatases, Oligonucleotide Array Sequence Analysis, Phosphoproteins, Protein-Serine-Threonine Kinases, Signal Transducing Adaptor Proteins, Signal Transduction, Tumor Cell Line
Source:Nature Genetics
Publisher:Nature Publishing Group
Page Range:872-877
Date:August 2015
Official Publication:https://doi.org/10.1038/ng.3349
PubMed:View item in PubMed

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