Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nat Genet. 2012 Oct;44(10):1126-30. doi: 10.1038/ng.2387. Epub 2012 Sep 2.
Neuroblastoma is a cancer of the sympathetic nervous system that accounts for approximately 10% of all pediatric oncology deaths. Here, we report a genome-wide association study of 2,817 neuroblastoma cases and 7,473 controls. We identified two new associations at 6q16, the first within HACE1 (rs4336470; combined P=2.7×10(-11); odds ratio 1.26, 95% confidence interval (CI) 1.18-1.35) and the second within LIN28B (rs17065417; combined P=1.2×10(-8); odds ratio 1.38, 95% CI 1.23-1.54). Expression of LIN28B and let-7 miRNA correlated with rs17065417 genotype in neuroblastoma cell lines, and we observed significant growth inhibition upon depletion of LIN28B, specifically in neuroblastoma cells that were homozygous for the risk allele. Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas were associated with worse overall survival (P=0.008 and 0.014, respectively). Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.
神经母细胞瘤是一种交感神经系统癌症，约占所有儿科肿瘤死亡人数的 10%。在这里，我们报告了对 2817 例神经母细胞瘤病例和 7473 例对照进行的全基因组关联研究。我们在 6q16 发现了两个新的关联，第一个是在 HACE1 内（rs4336470；合并 P=2.7×10(-11)；比值比 1.26，95%置信区间（CI）1.18-1.35），第二个是在 LIN28B 内（rs17065417；合并 P=1.2×10(-8)；比值比 1.38，95%CI 1.23-1.54）。LIN28B 和 let-7 miRNA 的表达与神经母细胞瘤细胞系中的 rs17065417 基因型相关，并且我们观察到 LIN28B 耗竭后显著的生长抑制，特别是在风险等位基因纯合的神经母细胞瘤细胞中。诊断性原发性神经母细胞瘤中低 HACE1 和高 LIN28B 表达与总生存期较差相关（P=0.008 和 0.014）。总之，这些数据表明 HACE1 和 LIN28B 中的常见变异影响神经母细胞瘤易感性，并表明这两个基因可能在疾病进展中起作用。
