Chromosome 6p22 locus associated with clinically aggressive neuroblastoma
Chromosome 6p22 locus associated with clinically aggressive neuroblastoma
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DOI：
10.1056/nejmoa0708698
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发表时间：
2008-06-12
影响因子：
158.5
通讯作者：
Hakonarson, Hakon
中科院分区：
文献类型：
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作者：
Maris, John M.;Mosse, Yael P.;Hakonarson, Hakon
背景资料：神经母细胞瘤是交感神经系统发育中的一种恶性疾病，最常影响幼儿，通常是致命的。它的原因是未知的。方法：我们进行了全基因组关联研究的第一个基因分型血液DNA样本从1032例神经母细胞瘤和2043对照受试者的欧洲血统使用的Illumina HumanHap 550珠芯片。来自三组独立的神经母细胞瘤患者的样本然后对720名患者和2128名对照组进行基因分型，以复制显著的相关性。我们观察到神经母细胞瘤与染色体带6p 22处的三个连续单核苷酸多态性（SNP）的常见次要等位基因（包含预测基因FLJ 22536和FLJ 44180）之间存在显著关联。（P=1.71 x 10（-9）至7.01 x 10（-10）;等位基因比值比，1.39至1.40）。最显著相关的SNP rs6939340的风险G等位基因的纯合性导致神经母细胞瘤发展的可能性增加（比值比，1.97; 95%置信区间，1.58至2.45）。随后对三个独立病例系列中的三个6p 22 SNP进行基因分型，证实了我们观察到的相关性（联合分析中rs6939340处的P=9.33 x 10（-15））。6p 22等位基因纯合子的神经母细胞瘤患者更容易发生转移性疾病（4期）（P=0.02）、肿瘤细胞中MYCN癌基因扩增（P=0.006）和疾病复发（P=0.01）。结论：染色体6p 22带的常见遗传变异与神经母细胞瘤易感性相关。
Background: 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.Methods: 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.Results: 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=1.71 x 10(-9) to 7.01 x 10(-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=9.33 x 10(-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).Conclusions: A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.