Neuroblastoma is a malignancy of the developing sympathetic nervous system that accounts for 12% of childhood cancer deaths. Like many childhood cancers, neuroblastoma shows 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 nonamplified 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 associated with phenotypes such as autism spectrum disorder (ASD). The postsynaptic adapter protein-coding gene, SHANK2, located on Chromosome 11q13, was disrupted by SVs in 14% of MYCN nonamplified 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.

中文翻译：

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体细胞结构变异针对神经发育基因，并将 SHANK2 鉴定为神经母细胞瘤中的肿瘤抑制因子。

神经母细胞瘤是一种发育中的交感神经系统恶性肿瘤，占儿童癌症死亡人数的 12%。与许多儿童癌症一样，与成人癌症相比，神经母细胞瘤表现出相对较少的体细胞单核苷酸变异（SNV）和小插入和缺失（indels）。在这里，我们结合肿瘤-正常对 ( n = 135) 的全基因组测序 (WGS) 和原发肿瘤 (n = 135) 的单核苷酸多态性 (SNP) 基因分型，评估了体细胞结构变异 (SV) 在神经母细胞瘤中的贡献。 = 914）。我们的研究设计允许跨平台进行正交验证和复制。高风险肿瘤之间的 SV 频率、类型和定位存在显着差异。MYCN非扩增高风险肿瘤总体上存在增加的 SV 负担，包括整个基因组中显着过量的串联重复事件。被 SV 断点破坏的基因在神经元谱系中富集，并与自闭症谱系障碍 (ASD) 等表型相关。位于染色体 11q13 上的突触后接头蛋白编码基因SHANK2在基于 WGS 的MYCN非扩增高风险肿瘤中被 SV 破坏，在 SNP 阵列队列中这一比例为 10%。SHANK2在人源性神经母细胞瘤细胞系和高风险神经母细胞瘤肿瘤中的表达较低。神经母细胞瘤细胞中SHANK2的强制表达导致显着的生长抑制（P = 2.6 × 10 ^-2至 3.4 × 10 ^-5），并在全反式视黄酸治疗后加速神经元分化（P = 3.1 × 10 ^-13至 2.4 × 10 ^-30 )。这些数据进一步定义了神经母细胞瘤中体细胞结构变异的复杂情况，并表明导致神经发育过程失调的事件（例如SHANK2失活）是这种儿童癌症肿瘤发生的关键介质。