title: Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression.
abstract: The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma.Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines.We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK.Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%.Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression.Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants.In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression.
authors.affiliation: University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy.|CEINGE Biotecnolgie Avanzate, Naples, Italy.
authors.forename: Vito Alessandro
authors.initials: VA
authors.lastname: Lasorsa
authors.affiliation: University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy.|CEINGE Biotecnolgie Avanzate, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Formicola
authors.affiliation: University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy.|CEINGE Biotecnolgie Avanzate, Naples, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Pignataro
authors.affiliation: University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy.|CEINGE Biotecnolgie Avanzate, Naples, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Cimmino
authors.affiliation: University of Bari, Department of Biology, Bari, Italy.
authors.forename: Francesco Maria
authors.initials: FM
authors.lastname: Calabrese
authors.affiliation: Hospital Sant Joan de Déu, Developmental Tumor Biology Laboratory and Department of Oncology, Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Mora
authors.affiliation: Pediatric Research Institute (IRP), Fondazione Città della Speranza, Neuroblastoma Laboratory, Padua, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Esposito
authors.affiliation: Pediatric Research Institute (IRP), Fondazione Città della Speranza, Neuroblastoma Laboratory, Padua, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Pantile
authors.affiliation: Pediatric Research Institute (IRP), Fondazione Città della Speranza, Neuroblastoma Laboratory, Padua, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Zanon
authors.affiliation: U.O.C. Bioterapie, IRCCS AOU San Martino-IST, National Cancer Research Institute, Genoa, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: De Mariano
authors.affiliation: U.O.C. Bioterapie, IRCCS AOU San Martino-IST, National Cancer Research Institute, Genoa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Longo
authors.affiliation: Children's Hospital of Philadelphia, Division of Oncology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
authors.affiliation: Hospital Sant Joan de Déu, Developmental Tumor Biology Laboratory and Department of Oncology, Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: de Torres
authors.affiliation: Pediatric Research Institute (IRP), Fondazione Città della Speranza, Neuroblastoma Laboratory, Padua, Italy.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.affiliation: University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy.|CEINGE Biotecnolgie Avanzate, Naples, Italy.
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
authors.affiliation: University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy.|CEINGE Biotecnolgie Avanzate, Naples, Italy.|IRCCS SDN, Istituto di Ricerca Diagnostica e Nucleare, Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Capasso
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D059472:Exome / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007223:Infant; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D016019:Survival Analysis
keywords: NGS; cancer driver genes; high risk; neuroblastoma; somatic mutation