Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility Loci.
Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility Loci.
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DOI：
10.1371/journal.pgen.1002026
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发表时间：
2011-03
期刊：
影响因子：
4.5
通讯作者：
Maris JM
中科院分区：
文献类型：
--
作者：
Nguyen le B;Diskin SJ;Capasso M;Wang K;Diamond MA;Glessner J;Kim C;Attiyeh EF;Mosse YP;Cole K;Iolascon A;Devoto M;Hakonarson H;Li HK;Maris JM
神经母细胞瘤是一种恶性肿瘤的发展交感神经系统是值得注意的是其表型多样性。高风险患者通常在诊断时具有广泛传播的疾病和较差的生存概率，但低风险患者通常具有局部肿瘤，几乎总是用很少或不用化疗治愈。我们的全基因组关联研究（GWAS）已经确定了FLJ22536，BARD 1和LMO 1中的常见变异与神经母细胞瘤显著相关，并且与高危疾病更密切相关。在这里，我们表明，一个关注低风险病例的GWAS发现DUSP12在1q23.3（P = 2.07×10−6），DDX4和IL31RA都在5q11.2（P = 2.94×10−6和6.54×10−7），以及HSD17B12在11p11.2（P = 4.20×10−7）的SNP与疾病的侵袭性较低。 这些数据证明了GWAS分析中稳健的表型数据的重要性，并确定了神经母细胞瘤的其他易感性变体。神经母细胞瘤是中枢神经系统以外最常见的实体瘤，占所有儿童癌症死亡率的10%。它具有独特的临床行为，并分为不同的风险组：高风险，中等风险和低风险。全基因组关联研究已经报道了许多易患高危神经母细胞瘤的遗传变异。这项研究的重点是低风险的神经母细胞瘤组，并确定了四个新的基因（DUSP12，DDX4，IL31RA和HSD17B12）在三个不同的基因组位置，窝藏致病变异。这项研究还报告了几个基因集，这些基因集在整个神经母细胞瘤中以及在高风险和低风险人群中富集。同样重要的是，这项研究采用了一种新的计算方法，将基因识别为致病变异，而不仅仅是一种单核苷酸多态性。该方法在神经母细胞瘤的全基因组关联信号检测中具有上级能力，在其他疾病的病例对照关联研究中具有很大的潜在应用价值。
Neuroblastoma is a malignant neoplasm of the developing sympathetic nervous system that is notable for its phenotypic diversity. High-risk patients typically have widely disseminated disease at diagnosis and a poor survival probability, but low-risk patients frequently have localized tumors that are almost always cured with little or no chemotherapy. Our genome-wide association study (GWAS) has identified common variants within FLJ22536, BARD1, and LMO1 as significantly associated with neuroblastoma and more robustly associated with high-risk disease. Here we show that a GWAS focused on low-risk cases identified SNPs within DUSP12 at 1q23.3 (P = 2.07×10−6), DDX4 and IL31RA both at 5q11.2 (P = 2.94×10−6 and 6.54×10−7 respectively), and HSD17B12 at 11p11.2 (P = 4.20×10−7) as being associated with the less aggressive form of the disease. These data demonstrate the importance of robust phenotypic data in GWAS analyses and identify additional susceptibility variants for neuroblastoma. Neuroblastoma is the most common solid tumor outside the central nervous system and is accountable for 10% of the mortality rate of all children's cancers. It has distinctive clinical behaviors and is categorized into different risk groups: high-risk, intermediate-risk, and low-risk. Genome-wide association studies have reported a number of genetic variations predisposing to high-risk neuroblastoma. This study focuses on the low-risk neuroblastoma group and identifies four novel genes (DUSP12, DDX4, IL31RA, and HSD17B12) at three distinct genomic positions that harbor disease-causing variants. This study also reports several gene sets that are enriched in overall neuroblastoma as well as in both high-risk and low-risk groups. Also of importance is that this study adopts a new computational method that identifies genes, instead of only one single nucleotide polymorphism, as disease-causing variants. Shown to have superior power of detection genome-wide association signals for neuroblastoma, the methodology presented in this study has great potential applications in case-control association studies in other diseases.
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影响因子：
158.5
作者：
Maris, John M.;Mosse, Yael P.;Hakonarson, Hakon
通讯作者：
Hakonarson, Hakon
影响因子：
1.8
作者：
Newton, Michael A.;Quintana, Fernando A.;Ahlquist, Paui
通讯作者：
Ahlquist, Paui
影响因子：
45.3
作者：
BRODEUR, GM;PRITCHARD, J;VOUTE, PA
通讯作者：
VOUTE, PA
影响因子：
8.8
作者：
Ambros, P. F.;Ambros, I. M.;Brodeur, G. M.;Haber, M.;Khan, J.;Nakagawara, A.;Schleiermacher, G.;Speleman, F.;Spitz, R.;London, W. B.;Cohn, S. L.;Pearson, A. D. J.;Maris, J. M.
通讯作者：
Maris, J. M.
影响因子：
56.9
作者：
BRODEUR, GM;SEEGER, RC;BISHOP, JM
通讯作者：
BISHOP, JM