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


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.

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Figure 1: Number and type of somatic alterations detected in each neuroblastoma case.
Figure 2: Genomic alterations affecting ARID1A and ARID1B.
Figure 3: Overall survival according to ARID1 gene mutation status.

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We thank the families and children with neuroblastoma who contributed to this work. We thank J. Maris for valuable input to this work, J. Ptak, N. Silliman, L. Dobbyn, M. Whalen, J. Schaefer and T. Mosbruger for technical assistance with sequencing analyses, L. Kann and S. Angiuoli of Personal Genome Diagnostics for targeted sequence analyses, the Children's Oncology Group (COG), W.B. London and the COG Statistics and Data Center, J. Gastier-Foster and the Neuroblastoma Reference Laboratory, N. Ramirez and the Biopathology Center, C. Winter and the Children's Hospital of Philadelphia (CHOP) Nucleic Acids Bank, and T. Woodburn and the COG Cell Line Repository. This work was generously supported by the St. Baldrick's Foundation for childhood cancer research, the Virginia and D.K. Ludwig Fund for Cancer Research, Swim Across America, an American Association for Cancer Research (AACR) Stand Up To Cancer–Dream Team Translational Cancer Research Grant and US National Institutes of Health (NIH) grant CA121113.

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Authors and Affiliations



C.P.R. established cell lines, and C.P.R. and X.L. purified DNA samples from which M.S. prepared next-generation DNA sequencing libraries. J.W. performed MYCN capture of genomic DNA libraries for massively parallel sequencing. M.S. and R.J.L. analyzed sequencing data for structural alterations. M.S., S.J., N.P., B.V., K.W.K. and V.E.V. sequenced next-generation DNA libraries and performed mutational analyses. A.B., G.P. and L.A.D. performed statistical analyses of clinical and sequencing data. M.S., R.J.L., B.V., K.W.K., V.E.V. and M.D.H. conceived the research and wrote the manuscript.

Corresponding authors

Correspondence to Victor E Velculescu or Michael D Hogarty.

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Competing interests

L.A.D., N.P., B.V., K.W.K. and V.E.V. are founders of Inostics and Personal Genome Diagnostics and are members of their Scientific Advisory Boards. L.A.D., N.P., B.V., K.W.K. and V.E.V. own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under university policy. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict-of-interest policies.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 2–4 and 8–10 and Supplementary Note (PDF 900 kb)

Supplementary Table 1

Description of neuroblastoma samples analyzed (XLSX 29 kb)

Supplementary Table 5

Somatic mutations identified in neuroblastoma (XLSX 37 kb)

Supplementary Table 6

Copy number alterations identified in neuroblastoma (XLSX 36 kb)

Supplementary Table 7

Somatic rearrangements identified in neuroblastoma (XLSX 43 kb)

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Sausen, M., Leary, R., Jones, S. et al. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet 45, 12–17 (2013).

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