Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma
- Gonzalo Lopez1,
- Karina L Conkrite2,
- Miriam Doepner3,
- Komal S Rathi2,
- Apexa Modi3,
- Zalman Vaksman2,
- Lance Farra4,
- Eric Hyson5,
- Moataz Noureddine6,
- Jun S. Wei7,
- Malcolm A Smith7,
- Shahab Asgharzadeh8,
- Robert Seeger8,
- Javed S. Khan9,
- Jaime M Guidry Auvil7,
- Daniela S. Gerhard9,
- John M Maris6 and
- Sharon J. Diskin2,10
- 1 Icahn School of Medicine at Mount Sinai;
- 2 Children's Hospital of Philadelphia;
- 3 Perelman School of Medicine, University of Pennsylvania;
- 4 University of Pittsburg;
- 5 Georgetown University;
- 6 Center for Childhood Cancer Research, Children's Hospital of Philadelphia;
- 7 NIH;
- 8 Children's Hospital Los Angeles;
- 9 National Cancer Institute
Abstract
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) of tumor-normal pairs (n=135) and single nucleotide polymorphism (SNP) genotyping of primary tumors (n=914). 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 significant 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 cells resulted in significant growth inhibition (P=2.6×10-2 to 3.4×10-5) and accelerated neuronal differentiation following treatment with all-trans retinoic acid (P=3.1×10-13 to 2.4×10-30). These data further define the complex landscape of somatic 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.
- Received July 25, 2019.
- Accepted August 7, 2020.
- Published by Cold Spring Harbor Laboratory Press
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