Ye Yuanqing, Wang Kenneth K, Gu Jian, Yang Hushan, Lin Jie, Ajani Jaffer A, Wu Xifeng
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Prev Res (Phila). 2008 Nov;1(6):460-9. doi: 10.1158/1940-6207.CAPR-08-0135.
MicroRNAs (miRNA) can act as oncogenes or tumor suppressors and modulate the expression of approximately one third of all human genes. To test the hypothesis that adverse alleles in miRNA-related genes may increase the risk for esophageal cancer, we assessed the associations between esophageal cancer risk and 41 potentially functional single nucleotide polymorphisms (SNP) in 26 miRNA-related genes in a case-control study of 346 Caucasian esophageal cancer patients (85.5% with esophageal adenocarcinoma) and 346 frequency-matched (age, gender, and ethnicity) controls. Seven SNPs were significantly associated with esophageal cancer risk. The most notable finding was that the SNP rs6505162, which is located in the pre-mir423 region, was associated with a per-allele odds ratio of 0.64 [95% confidence interval (95% CI), 0.51-0.80; P for trend < 0.0001]. This association remained significant after we corrected for multiple comparisons. A common haplotype of the GEMIN4 gene was associated with a significantly reduced risk of esophageal cancer (odds ratio, 0.65; 95% CI, 0.42-0.99). We did a combined unfavorable genotype analysis to further evaluate the cumulative effects of the promising (risk associated) SNPs. In comparison with the low-risk group (fewer than three unfavorable genotypes), the medium-risk group (three unfavorable genotypes) had a 2.00-fold (95% CI, 1.31-3.08) increased risk and the high-risk group (more than three unfavorable genotypes) had a 3.14-fold (95% CI, 2.03-4.85) increased risk (P for trend < 0.0001). Results for the risk of esophageal adenocarcinoma were similar to the overall risk results. The present study provides the first evidence that miRNAs may affect esophageal cancer risk in general and that specific genetic variants in miRNA-related genes may affect esophageal cancer risk individually and jointly.
微小RNA（miRNA）可作为癌基因或肿瘤抑制因子，调控约三分之一的人类基因表达。为验证miRNA相关基因中的有害等位基因可能增加食管癌风险这一假说，我们在一项病例对照研究中，评估了346例白种人食管癌患者（85.5%为食管腺癌）和346例频率匹配（年龄、性别和种族）的对照中，食管癌风险与26个miRNA相关基因中41个潜在功能性单核苷酸多态性（SNP）之间的关联。7个SNP与食管癌风险显著相关。最显著的发现是，位于pre - mir423区域的SNP rs6505162，其每等位基因优势比为0.64 [95%置信区间（95%CI），0.51 - 0.80；趋势P < 0.0001]。在进行多重比较校正后，这种关联仍然显著。GEMIN4基因的一种常见单倍型与食管癌风险显著降低相关（优势比，0.65；95%CI，0.42 - 0.99）。我们进行了综合不利基因型分析，以进一步评估有前景的（与风险相关的）SNP的累积效应。与低风险组（少于三个不利基因型）相比，中风险组（三个不利基因型）的风险增加了2.00倍（95%CI，1.31 - 3.08），高风险组（多于三个不利基因型）的风险增加了3.14倍（95%CI，2.03 - 4.85）（趋势P < 0.0001）。食管腺癌风险的结果与总体风险结果相似。本研究首次提供证据表明，miRNA总体上可能影响食管癌风险，且miRNA相关基因中的特定遗传变异可能单独和共同影响食管癌风险。
