title: Integrative Genome-Scale Analysis Identifies Epigenetic Mechanisms of Transcriptional Deregulation in Unfavorable Neuroblastomas.
abstract: The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility of epigenetic involvement in pathogenesis. In pursuit of this hypothesis, we took an integrative approach to analyze the methylomes, transcriptomes, and copy number variations in 105 cases of neuroblastoma, complemented by primary tumor- and cell line-derived global histone modification analyses and epigenetic drug treatment in vitro We found that DNA methylation patterns identify divergent patient subgroups with respect to survival and clinicobiologic variables, including amplified MYCN Transcriptome integration and histone modification-based definition of enhancer elements revealed intragenic enhancer methylation as a mechanism for high-risk-associated transcriptional deregulation. Furthermore, in high-risk neuroblastomas, we obtained evidence for cooperation between PRC2 activity and DNA methylation in blocking tumor-suppressive differentiation programs. Notably, these programs could be re-activated by combination treatments, which targeted both PRC2 and DNA methylation. Overall, our results illuminate how epigenetic deregulation contributes to neuroblastoma pathogenesis, with novel implications for its diagnosis and therapy. Cancer Res; 76(18); 5523-37. ©2016 AACR.
authors.affiliation: Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany. k.henrich@dkfz frank.westermann@dkfz.de.
authors.forename: Kai-Oliver
authors.initials: KO
authors.lastname: Henrich
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany & Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bender
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Maral
authors.initials: M
authors.lastname: Saadati
authors.affiliation: Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dreidax
authors.affiliation: Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Gartlgruber
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Chunxuan
authors.initials: C
authors.lastname: Shao
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center, Institute of Pharmacy and Molecular Biotechnology, Bioquant, University of Heidelberg, Germany.
authors.forename: Carl
authors.initials: C
authors.lastname: Herrmann
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Wiesenfarth
authors.affiliation: Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Martha
authors.initials: M
authors.lastname: Parzonka
authors.affiliation: Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Wehrmann
authors.affiliation: Department of Pediatric Oncology, University Children's Hospital, and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Duffy
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Bell
authors.affiliation: Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Alica
authors.initials: A
authors.lastname: Torkov
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany & Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany. k.henrich@dkfz frank.westermann@dkfz.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
mesh_terms: D000293:Adolescent; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic; D059467:Transcriptome; D055815:Young Adult
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein