对基因变异在滤泡性淋巴瘤生存中的作用进行全面评估。
A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival.
作者信息
Baecklund Fredrik, Foo Jia-Nee, Bracci Paige, Darabi Hatef, Karlsson Robert, Hjalgrim Henrik, Rosenquist Richard, Adami Hans-Olov, Glimelius Bengt, Melbye Mads, Conde Lucia, Liu Jianjun, Humphreys Keith, Skibola Christine F, Smedby Karin E
机构信息
Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
Department of Oncology, Karolinska University Hospital Solna, Stockholm, Sweden.
出版信息
BMC Med Genet. 2014 Oct 8;15:113. doi: 10.1186/s12881-014-0113-6.
BACKGROUND
Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed.
METHODS
We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of ~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999-2002 and in the United States 2001-2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model.
RESULTS
In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0 ×10(-8)). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom = 3.17, 95% CI 2.09-4.79, prandom = 5.24 ×10(-8)). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival.
CONCLUSIONS
The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.
背景
滤泡性淋巴瘤（FL）患者的生存期差异很大，即使在由肿瘤分级和滤泡性淋巴瘤国际预后指数定义的预后组中也是如此。研究表明，种系单核苷酸多态性（SNP）可能包含预后信息，但仍需进一步研究。
方法
我们采用两种方法探讨SNP与FL预后之间的关联：1）对约30万个SNP进行两项独立的全基因组关联研究（GWAS），随后进行荟萃分析，纳入1999 - 2002年在丹麦/瑞典以及2001 - 2006年在美国诊断的586例FL患者；2）对丹麦/瑞典队列（N = 373）中先前与FL预后相关的22个候选基因变异进行研究。我们在多变量Cox回归模型中，通过风险比（HR）和95%置信区间（CI）估计淋巴瘤特异性死亡时间（方法1和2）以及淋巴瘤进展时间（方法2）。
结果
在GWAS荟萃分析中，使用随机效应模型，在全基因组显著水平（p < 5.0×10⁻⁸）下，没有变异与淋巴瘤特异性死亡相关。在ABCA10和ABCA6基因附近的17q24上紧密连锁的SNP观察到最强关联（rs10491178，HR随机 = 3.17，95% CI 2.09 - 4.79，p随机 = 5.24×10⁻⁸）。ABCA10和ABCA6基因属于编码ABC转运蛋白的基因家族，与多药耐药有关。与先前的一项研究一致，CD46中的rs2466571（HR = 0.73，95% CI 0.58 - 0.91，p = 0.006）与淋巴瘤进展呈名义上的关联，IL8中的两个高度连锁的SNP（rs4073，HR = 0.78，95% CI 0.62 - 0.97，p = 0.02；rs2227307，HR = 0.75，95% CI 0.60 - 0.94，p = 0.01）也是如此，它们先前与总生存期相关。
结论
结果表明多药耐药在FL生存中可能起作用，并进一步证明CD46和IL8中的基因变异可能对FL预后有影响。我们的发现需要在其他独立人群或更大规模的多中心GWAS中进一步证实。
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