Section of Genetic Medicine, University of Chicago, 900 E 57th St, Rm 3220F, Chicago, IL 60637, USA.
J Natl Cancer Inst. 2013 Feb 20;105(4):302-9. doi: 10.1093/jnci/djs503. Epub 2012 Dec 14.
Black patients with neuroblastoma have a higher prevalence of high-risk disease and worse outcome than white patients. We sought to investigate the relationship between genetic variation and the disparities in survival observed in neuroblastoma.
The analytic cohort was composed of 2709 patients. Principal components were used to assign patients to genomic ethnic clusters for survival analyses. Locus-specific ancestry was calculated for use in association analysis. The shorter spans of linkage disequilibrium in African populations may facilitate the fine mapping of causal variants in regions previously implicated by genome-wide association studies conducted primarily in patients of European descent. Thus, we evaluated 13 single nucleotide polymorphisms known to be associated with susceptibility to high-risk neuroblastoma from genome-wide association studies and all variants with highly divergent allele frequencies in reference African and European populations near the known susceptibility loci. All statistical tests were two-sided.
African genomic ancestry was associated with high-risk neuroblastoma (P = .007) and lower event-free survival (P = .04, hazard ratio = 1.4, 95% confidence interval = 1.05 to 1.80). rs1033069 within SPAG16 (sperm associated antigen 16) was determined to have higher risk allele frequency in the African reference population and statistically significant association with high-risk disease in patients of European and African ancestry (P = 6.42 × 10(-5), false discovery rate < 0.0015) in the overall cohort. Multivariable analysis using an additive model demonstrated that the SPAG16 single nucleotide polymorphism contributes to the observed ethnic disparities in high-risk disease and survival.
Our study demonstrates that common genetic variation influences neuroblastoma phenotype and contributes to the ethnic disparities in survival observed and illustrates the value of trans-population mapping.
与白人患者相比，患有神经母细胞瘤的黑人患者具有更高的高危疾病发生率和更差的预后。我们试图研究遗传变异与神经母细胞瘤观察到的生存差异之间的关系。
分析队列由 2709 名患者组成。主成分用于将患者分配到生存分析的基因组种族群中。特定基因座的祖先被计算出来，用于关联分析。非洲人群中较短的连锁不平衡跨度可能有助于在以前由主要在欧洲血统患者进行的全基因组关联研究中发现的与高危神经母细胞瘤易感性相关的区域进行精细映射。因此，我们评估了 13 个单核苷酸多态性，这些多态性已知与易患高危神经母细胞瘤相关，并且在全基因组关联研究中，所有与已知易感性位点附近的非洲和欧洲参考人群中的高度分化等位基因频率相关的变体。所有统计检验均为双侧检验。
非洲基因组祖先与高危神经母细胞瘤相关（P =.007），无事件生存时间较低（P =.04，风险比 = 1.4，95%置信区间 = 1.05 至 1.80）。位于 SPAG16（精子相关抗原 16）内的 rs1033069 在非洲参考人群中的高风险等位基因频率更高，并且在具有欧洲和非洲祖先的患者中与高危疾病具有统计学显著关联（P = 6.42×10(-5)，假发现率<0.0015）在整个队列中。使用加性模型的多变量分析表明，SPAG16 单核苷酸多态性导致了高危疾病和生存观察到的种族差异。
我们的研究表明，常见的遗传变异影响神经母细胞瘤表型，并导致观察到的生存种族差异，说明了跨人群映射的价值。
