Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Carcinogenesis. 2010 Oct;31(10):1805-12. doi: 10.1093/carcin/bgq168. Epub 2010 Aug 23.
We took a polygenic approach to evaluate the effects of 41 potentially functional single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs)-related genes on survival and recurrence among renal cell carcinoma (RCC) patients. During a median follow-up of 21.8 months, among 316 RCC patients, 64 died and 56 developed recurrence. In single-SNP analysis, we identified seven SNPs significantly associated with RCC survival and five SNPs with recurrence. The most significant associations were SNPs in GEMIN4 with the variant alleles of both rs7813 and rs910925 associated with 1.74-fold [95% confidence interval (CI) = 1.15-2.62] increased risk of death, whereas the variant allele of rs3744741 conferred a decreased risk of death [hazard ratio (HR) = 0.39; 95% CI = 0.19-0.77]. Several SNPs belonging to the pre-miRNA and were identified to be significantly associated with RCC recurrence. Haplotypes of DICER and DROSHA were also associated with altered patient survival and recurrence. More importantly, we observed cumulative effects of multiple SNPs on RCC survival. Compared with subjects carrying zero to two unfavorable genotypes, those carrying three to five and six and more unfavorable genotypes had an increased risk of death with a HR of 2.49 (95% CI = 1.24-5.00) and 6.66 (95% CI = 2.49-17.86), respectively, with significant dose-response trend (P for trend<0.001). As the first study of miRNA-related genetic polymorphisms on RCC clinical outcome, our results strongly suggested that miRNA-related SNPs may impact the recurrence and survival in RCC patients. Future investigation in larger populations and functional characterizations are necessary to validate these results.
我们采用多基因方法评估了 41 个潜在功能单核苷酸多态性（SNP）在 miRNA（miRNA）相关基因对肾细胞癌（RCC）患者生存和复发的影响。在中位数为 21.8 个月的随访期间，在 316 名 RCC 患者中，有 64 人死亡，56 人复发。在单 SNP 分析中，我们确定了 7 个与 RCC 生存显著相关的 SNP 和 5 个与复发相关的 SNP。最显著的关联是 GEMIN4 中的 SNP，其变体等位基因 rs7813 和 rs910925 与死亡风险增加 1.74 倍相关（95%置信区间[CI] = 1.15-2.62），而 rs3744741 的变体等位基因降低了死亡风险（风险比[HR] = 0.39；95%CI = 0.19-0.77）。属于前 miRNA 的几个 SNP 也被确定与 RCC 复发显著相关。DICER 和 DROSHA 的单倍型也与患者生存和复发的改变有关。更重要的是，我们观察到多个 SNP 对 RCC 生存的累积效应。与携带零到两种不利基因型的受试者相比，携带三到五种和六种及以上不利基因型的受试者死亡风险增加，HR 分别为 2.49（95%CI = 1.24-5.00）和 6.66（95%CI = 2.49-17.86），且具有显著的剂量反应趋势（P<0.001）。作为 miRNA 相关遗传多态性对 RCC 临床结局影响的第一项研究，我们的结果强烈表明，miRNA 相关 SNP 可能影响 RCC 患者的复发和生存。需要在更大的人群中进行进一步的研究和功能特征分析，以验证这些结果。
