TY - JOUR
T1 - Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma
AU - Sausen, Mark
AU - Leary, Rebecca J.
AU - Jones, Siân
AU - Wu, Jian
AU - Reynolds, C. Patrick
AU - Liu, Xueyuan
AU - Blackford, Amanda
AU - Parmigiani, Giovanni
AU - Diaz, Luis A.
AU - Papadopoulos, Nickolas
AU - Vogelstein, Bert
AU - Kinzler, Kenneth W.
AU - Velculescu, Victor E.
AU - Hogarty, Michael D.
N1 - Funding Information:
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.
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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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U2 - 10.1038/ng.2493
DO - 10.1038/ng.2493
M3 - Article
C2 - 23202128
AN - SCOPUS:84871982155
SN - 1061-4036
VL - 45
SP - 12
EP - 17
JO - Nature genetics
JF - Nature genetics
IS - 1
ER -