PT - JOURNAL ARTICLE AU - Gonzalo Lopez AU - Karina L. Conkrite AU - Miriam Doepner AU - Komal S. Rathi AU - Apexa Modi AU - Zalman Vaksman AU - Lance M. Farra AU - Eric Hyson AU - Moataz Noureddine AU - Jun S. Wei AU - Malcolm A. Smith AU - Shahab Asgharzadeh AU - Robert C. Seeger AU - Javed Khan AU - Jaime Guidry Auvil AU - Daniela S. Gerhard AU - John M. Maris AU - Sharon J. Diskin TI - Structural variation targets neurodevelopmental genes and identifies <em>SHANK2</em> as a tumor suppressor in neuroblastoma AID - 10.1101/572248 DP - 2019 Jan 01 TA - bioRxiv PG - 572248 4099 - http://biorxiv.org/content/early/2019/03/13/572248.short 4100 - http://biorxiv.org/content/early/2019/03/13/572248.full AB - Neuroblastoma, like many childhood cancers, exhibits a relative paucity of somatic single nucleotide variants (SNVs). Here, we assess the contribution of structural variation (SV) in neuroblastoma using a combination of whole genome sequencing (WGS; n=135) and single nucleotide polymorphism (SNP) genotyping (n=914) of matched tumor-normal pairs. Our study design provided means for orthogonal validation of SVs as well as validation across genomic platforms. SV frequency, type, and localization varied significantly among high-risk tumors, with MYCN non-amplified tumors harboring an increased SV burden overall (P=1.12×10−5). Genes disrupted by SV breakpoints were enriched in neuronal lineages and autism spectrum disorder. The postsynaptic adapter protein-coding gene SHANK2, located on chromosome 11q13, was disrupted by SVs in 14% and 10% of MYCN non-amplified high-risk tumors based on WGS and SNP array cohorts, respectively. Forced expression of SHANK2 in neuroblastoma cell models resulted in significant growth inhibition (P=2.62×10−2 to 3.4×10−5) and accelerated neuronal differentiation following treatment with all-trans retinoic acid (P=3.08×10−13 to 2.38×10−30). These data further define the complex landscape of structural variation in neuroblastoma and suggest that events leading to deregulation of neurodevelopmental processes, such as inactivation of SHANK2, are key mediators of tumorigenesis.