Data from Somatic Mutations Enriched in Cis-Regulatory Elements Affect Genes Involved in Embryonic Development and Immune System Response in Neuroblastoma
Abstract
Abstract Noncoding cis-regulatory variants have gained interest as cancer drivers, yet progress in understanding their significance is hindered by the numerous challenges and limitations of variant prioritization. To overcome these limitations, we focused on active cis-regulatory elements (aCRE) to design a customized panel for the deep sequencing of 56 neuroblastoma tumor and normal DNA sample pairs. To search for driver mutations, aCREs were defined by reanalysis of H3K27ac chromatin immunoprecipitation sequencing peaks in 25 neuroblastoma cell lines. These regulatory genomic regions were tested for an excess of somatic mutations and assessed for statistical significance using a global approach that accounted for chromatin accessibility and replication timing. Additional validation was provided by whole genome sequence analysis of 151 neuroblastomas. Analysis of HiC data determined the presence of candidate target genes interacting with mutated regions. An excess of somatic mutations in aCREs of diverse genes were identified, including IPO7, HAND2, and ARID3A. CRISPR-Cas9 editing was utilized to assess the functional consequences of mutations in the IPO7-aCRE. Patients with noncoding mutations in aCREs showed inferior overall and event-free survival independent of age at diagnosis, stage, risk stratification, and MYCN status. Expression of aCRE-interacting genes correlated strongly with negative prognostic markers and low survival rates. Moreover, a convergence between the biological functions of aCRE target genes and transcription factors with mutated binding motifs was associated with embryonic development and immune system response. Overall, this strategy enabled the identification of somatic mutations in regulatory elements that collectively promote neuroblastoma tumorigenesis. Significance: Assessment of noncoding cis-regulatory variants and long-range interaction data highlight the combined effect of somatic mutations in regulatory elements in driving neuroblastoma.
Authors 9
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CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) · University of Naples Federico II
Affiliation as printed
CEINGE Biotecnologie Avanzate. Via Gaetano Salvatore 486, 80145 Napoli, Italy
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit a degli Studi di Napoli Federico II, Via G. Salvatore, 486, Napoli, Select State/Province, 80145, Italy
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CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) · University of Naples Federico II
Affiliation as printed
CEINGE Biotecnologie Avanzate. Via Gaetano Salvatore 486, 80145 Napoli, Italy
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit a degli Studi di Napoli Federico II, Via G. Salvatore, 486, Napoli, Select State/Province, 80145, Italy
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CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) · University of Naples Federico II
Affiliation as printed
CEINGE Biotecnologie Avanzate. Via Gaetano Salvatore 486, 80145 Napoli, Italy
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit a degli Studi di Napoli Federico II, Via G. Salvatore, 486, Napoli, Select State/Province, 80145, Italy
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University of Milan · European School of Molecular Medicine
Affiliation as printed
European School of Molecular Medicine, Universit a degli Studi di Milano, Milano, Italy
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Hospital Sant Joan de Déu Barcelona
Affiliation as printed
Hospital Sant Joan de D eu, Developmental Tumor Biology Laboratory and Department of Oncology, Esplugues de Llobregat, Barcelona, Spain
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Universitätsklinikum Aachen · Città della Speranza Foundation · RWTH Aachen University
Affiliation as printed
Department of Dental Materials and Bio-materials Research, RWTH Aachen University Hospital, Germany
Neuroblastoma Laboratory, Istituto di Ricerca Pediatrica Fondazione Citt a della Speranza, Padova, Italy
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Città della Speranza Foundation
Affiliation as printed
Neuroblastoma Laboratory, Istituto di Ricerca Pediatrica Fondazione Citt a della Speranza, Padova, Italy
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CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) · University of Naples Federico II
Affiliation as printed
CEINGE Biotecnologie Avanzate. Via Gaetano Salvatore 486, 80145 Napoli, Italy
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit a degli Studi di Napoli Federico II, Via G. Salvatore, 486, Napoli, Select State/Province, 80145, Italy
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CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) · University of Naples Federico II
Affiliation as printed
CEINGE Biotecnologie Avanzate. Via Gaetano Salvatore 486, 80145 Napoli, Italy
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit a degli Studi di Napoli Federico II, Via G. Salvatore, 486, Napoli, Select State/Province, 80145, Italy
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