title: Mutational dynamics between primary and relapse neuroblastomas.
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.
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Alexander
authors.identifier: 0000000176707529
authors.initials: A
authors.lastname: Schramm
authors.affiliation: Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Köster
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Yassen
authors.initials: Y
authors.lastname: Assenov
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Althoff
authors.affiliation: 1] Department of Translational Genomics, University of Cologne, Cologne, Germany. [2] Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Mahlow
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Odersky
authors.affiliation: Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Beisser
authors.affiliation: Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Ernst
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anton G
authors.initials: AG
authors.lastname: Henssen
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Stephan
authors.affiliation: Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Schröder
authors.affiliation: NEO New Oncology, Cologne, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Heukamp
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital, Cologne, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Engesser
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital, Cologne, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kahlert
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital, Cologne, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Theissen
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital, Cologne, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital, Cologne, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Roels
authors.affiliation: 1] Cologne Center for Genomics, University of Cologne, Cologne, Germany. [2] Human Genetics, University Hospital Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: 1] Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. [2] Cologne Center for Genomics, University of Cologne, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany.
authors.forename: Kathy
authors.initials: K
authors.lastname: Astrahantseff
authors.affiliation: NEO New Oncology, Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gloeckner
authors.affiliation: Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.affiliation: 1] Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2] German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Computer Science, TU Dortmund, Dortmund, Germany.
authors.forename: Sangkyun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Pediatric Oncology and Hematology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
authors.affiliation: Neuroblastoma Genomics, B087, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Kai-Oliver
authors.initials: KO
authors.lastname: Henrich
authors.affiliation: Neuroblastoma Genomics, B087, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Gartlgruber
authors.affiliation: Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.affiliation: Neuroblastoma Genomics, B087, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.affiliation: 1] Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. [2] Computer Science, TU Dortmund, Dortmund, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Rahmann
authors.affiliation: 1] Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. [2] Pediatric Oncology and Hematology, University Children's Hospital, Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: 1] Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany. [2] German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.affiliation: 1] Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany. [2] Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany. [3] German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004265:DNA Helicases / Q000235:genetics; D059472:Exome / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D000090683:Hippo Signaling Pathway; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases; C093261:PTPN14 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D004265:DNA Helicases; C471926:CHD5 protein, human