title: Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma.
abstract: Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma, we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases) and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average, each tumor had 19 somatic alterations in coding genes (range of 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of the chromatin-remodeling genes ARID1A and ARID1B were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight the dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of patients with neuroblastoma.
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sausen
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Leary
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Liu
authors.forename: Amanda
authors.initials: A
authors.lastname: Blackford
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome; D020869:Gene Expression Profiling; D023061:Gene Order; D023281:Genomics; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C112476:ARID1A protein, human; C497837:ARID1B protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors