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  - Somatic 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/2019/07/25/572248.short
4100  - http://biorxiv.org/content/early/2019/07/25/572248.full
AB  - Neuroblastoma is a malignancy of the developing sympathetic nervous system that accounts for 12% of childhood cancer deaths. Like many childhood cancers, neuroblastoma exhibits a relative paucity of somatic single nucleotide variants (SNVs) and small insertions and deletions (indels) compared to adult cancers. Here, we assessed the contribution of somatic 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 allowed for orthogonal validation and replication across platforms. SV frequency, type, and localization varied significantly among high-risk tumors. MYCN non-amplified high-risk tumors harbored an increased SV burden overall, including a substantial excess of tandem-duplication events across the genome. Genes disrupted by SV breakpoints were enriched in neuronal lineages and autism spectrum disorder (ASD). The postsynaptic adapter protein-coding gene SHANK2, located on chromosome 11q13, was disrupted by SVs in 14% of MYCN non-amplified high-risk tumors based on WGS and 10% in the SNP array cohort. Expression of SHANK2 was low across human-derived neuroblastoma cell lines and high-risk neuroblastoma tumors. 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 in this childhood cancer.