Maris John M, Mosse Yael P, Bradfield Jonathan P, Hou Cuiping, Monni Stefano, Scott Richard H, Asgharzadeh Shahab, Attiyeh Edward F, Diskin Sharon J, Laudenslager Marci, Winter Cynthia, Cole Kristina A, Glessner Joseph T, Kim Cecilia, Frackelton Edward C, Casalunovo Tracy, Eckert Andrew W, Capasso Mario, Rappaport Eric F, McConville Carmel, London Wendy B, Seeger Robert C, Rahman Nazneen, Devoto Marcella, Grant Struan F A, Li Hongzhe, Hakonarson Hakon
Division of Oncology and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.
N Engl J Med. 2008 Jun 12;358(24):2585-93. doi: 10.1056/NEJMoa0708698. Epub 2008 May 7.
Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known.
We performed a genomewide association study by first genotyping blood DNA samples from 1032 patients with neuroblastoma and 2043 control subjects of European descent using the Illumina HumanHap550 BeadChip. Samples from three independent groups of patients with neuroblastoma (a total of 720 patients) and 2128 control subjects were then genotyped to replicate significant associations.
We observed a significant association between neuroblastoma and the common minor alleles of three consecutive single-nucleotide polymorphisms (SNPs) at chromosome band 6p22 and containing the predicted genes FLJ22536 and FLJ44180 (P=1.71x10(-9) to 7.01x10(-10); allelic odds ratio, 1.39 to 1.40). Homozygosity for the at-risk G allele of the most significantly associated SNP, rs6939340, resulted in an increased likelihood of the development of neuroblastoma (odds ratio, 1.97; 95% confidence interval, 1.58 to 2.45). Subsequent genotyping of the three 6p22 SNPs in three independent case series confirmed our observation of an association (P=9.33x10(-15) at rs6939340 for joint analysis). Patients with neuroblastoma who were homozygous for the risk alleles at 6p22 were more likely to have metastatic (stage 4) disease (P=0.02), amplification of the MYCN oncogene in the tumor cells (P=0.006), and disease relapse (P=0.01).
A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.
神经母细胞瘤是一种发生于发育中的交感神经系统的恶性疾病，最常影响幼儿，且往往致命。其病因尚不清楚。
我们进行了一项全基因组关联研究，首先使用Illumina HumanHap550 BeadChip对1032例神经母细胞瘤患者和2043例欧洲裔对照者的血液DNA样本进行基因分型。然后对来自三个独立神经母细胞瘤患者组（共720例患者）和2128例对照者的样本进行基因分型，以重复显著关联。
我们观察到神经母细胞瘤与位于6号染色体22区带的三个连续单核苷酸多态性（SNP）的常见次要等位基因之间存在显著关联，这些SNP包含预测基因FLJ22536和FLJ44180（P = 1.71×10⁻⁹至7.01×10⁻¹⁰；等位基因优势比，1.39至1.40）。与神经母细胞瘤关联最显著的SNP rs6939340的风险G等位基因纯合性导致神经母细胞瘤发生的可能性增加（优势比，1.97；95%置信区间，1.58至2.45）。随后在三个独立病例系列中对6号染色体22区带的三个SNP进行基因分型，证实了我们对关联的观察结果（联合分析时rs6939340的P = 9.33×10⁻¹⁵）。6号染色体22区带风险等位基因纯合的神经母细胞瘤患者更有可能患有转移性（4期）疾病（P = 0.02）、肿瘤细胞中MYCN癌基因扩增（P = 0.006）以及疾病复发（P = 0.01）。
6号染色体22区带的一种常见基因变异与神经母细胞瘤易感性相关。
