Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma

• Published in: Nature genetics Vol. 45; no. 1; pp. 12 - 17
• Main Authors: Sausen, Mark, Leary, Rebecca J, Jones, Siân, Wu, Jian, Reynolds, C Patrick, Liu, Xueyuan, Blackford, Amanda, Parmigiani, Giovanni, Diaz, Luis A, Papadopoulos, Nickolas, Vogelstein, Bert, Kinzler, Kenneth W, Velculescu, Victor E, Hogarty, Michael D
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2013; Nature Publishing Group
• Subjects: 631/1647/2217; 631/208/68; 631/378/1689/1690; Agriculture; Animal Genetics and Genomics; Biomarkers, Tumor - genetics; Biomedicine; Cancer Research; Care and treatment; Cell Line, Tumor; Child; Deoxyribonucleic acid; Diagnosis; Disease detection; DNA; DNA Copy Number Variations; DNA sequencing; DNA-Binding Proteins - genetics; Exome; Gene Expression Profiling; Gene Function; Gene mutations; Gene Order; Genetic testing; Genetics; Genomes; Genomics; Human Genetics; Humans; Identification and classification; Kinases; Medical research; Methods; Mutation; Neuroblastoma; Neuroblastoma - genetics; Neuroblastoma - mortality; Nuclear Proteins - genetics; Nucleotide sequencing; Pediatrics; Sequence Analysis, DNA; Transcription Factors - genetics; Tumors; China
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.2493

Victor Velculescu, Michael Hogarty and colleagues report whole-genome and exome sequences of neuroblastoma, the most common solid tumor in children. They identify recurrent somatic mutations in the chromatin-remodeling genes ARID1A and ARID1B . 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.