BACKGROUND Neuroblastoma is a biologically and clinically heterogeneous disease. Based on recent studies demonstrating an association between the primary tumor site, prognosis, and commonly measured tumor biological features, we hypothesized that neuroblastomas arising in different sites would show distinct genomic features reflective of the developmental biology of the sympathicoadrenal nervous system. METHODS We first compared genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) compared to thoracic sympathetic ganglia (n = 118). We also evaluated association of common germline variation with these primary sites in 1027 European-American neuroblastoma patients. RESULTS We observed higher rates of MYCN amplification, chromosome 1q gain, and chromosome 11q deletion among adrenal tumors, which were highly predictive of functional RNA signatures. Surprisingly, thoracic neuroblastomas were more likely to harbor ALK driver mutations than adrenal cases among all cases (odds ratio = 1.89, 95% confidence interval = 1.04 to 3.43), and among cases without MYCN amplification (odds ratio = 2.86, 95% confidence interval = 1.48 to 5.49). Common germline single nucleotide polymorphisms (SNPs) in BARD1 (previously associated with high-risk neuroblastoma) were found to be strongly associated with predisposition for origin at adrenal, rather than thoracic, sites. CONCLUSIONS Neuroblastomas arising in the adrenal gland are more likely to harbor structural DNA aberrations including MYCN amplification, whereas thoracic tumors show defects in mitotic checkpoints resulting in hyperdiploidy. Despite the general association of ALK mutations with high-risk disease, thoracic tumors are more likely to harbor gain-of-function ALK aberrations. Site of origin is likely reflective of stage of sympathetic nervous system development when malignant transformation occurs and is a surrogate for underlying tumor biology.

中文翻译：

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胸腺和肾上腺神经母细胞瘤基因组概况和结果的差异。

背景技术神经母细胞瘤是生物学和临床上的异质性疾病。基于最近的研究表明原发肿瘤部位，预后和通常测量的肿瘤生物学特征之间的关联，我们假设在不同部位出现的神经母细胞瘤将显示出独特的基因组特征，反映出交感神经上皮神经系统的发育生物学。方法我们首先比较了起源于肾上腺的原发性诊断性神经母细胞瘤（n = 646）与胸交感神经节（n = 118）的基因组和表观基因组数据。我们还评估了1027名欧美神经母细胞瘤患者常见种系变异与这些主要部位的相关性。结果我们观察到肾上腺肿瘤中MYCN扩增，染色体1q扩增和染色体11q缺失的发生率更高，可以高度预测功能性RNA的特征。出乎意料的是，在所有病例中（优势比= 1.89，95％置信区间= 1.04至3.43），在没有MYCN扩增的病例中（优势比= 2.86，95％置信区间），胸膜神经母细胞瘤更可能携带ALK驱动突变。 = 1.48至5.49）。已发现BARD1中的常见种系单核苷酸多态性（SNP）（以前与高危神经母细胞瘤有关）与肾上腺而不是胸腔部位的易感性密切相关。结论肾上腺神经母细胞瘤更有可能带有包括MYCN扩增在内的结构性DNA畸变，而胸腔肿瘤在有丝分裂检查点显示缺陷，从而导致超二倍体。尽管ALK突变与高危疾病有着广泛的联系，但是胸腔肿瘤更有可能出现功能性ALK畸变。当发生恶性转化时，起源部位可能反映了交感神经系统发育的阶段，并且是潜在肿瘤生物学的替代物。