Genetic variants in MicroRNA biosynthesis pathways and binding sites modify ovarian cancer risk, survival, and treatment response.
Genetic variants in MicroRNA biosynthesis pathways and binding sites modify ovarian cancer risk, survival, and treatment response.
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DOI：
10.1158/0008-5472.can-10-0130
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Lu K
中科院分区：
文献类型：
--
作者：
Liang D;Meyer L;Chang DW;Lin J;Pu X;Ye Y;Gu J;Wu X;Lu K
MicroRNAs(MiRNA)在肿瘤发生中发挥重要作用。MiRNA加工基因和miRNA结合位点的遗传变异可能影响miRNA的生物发生和miRNAs对其靶基因的调控作用，从而促进肿瘤的发生。本研究分析了339例卵巢癌患者和349例健康对照的miRNA加工基因和miRNA结合位点的226个单核苷酸多态(SNP)，以评估其与癌症风险、总生存期和治疗反应的关系。13个基因多态与风险显著相关。最显著的是GEMIN4中的2个连锁SNPs(R2=0.99)、rs2740351和rs7813[优势比(OR)=0.71；95%可信区间(CI)，0.57~0.87和OR=0.71；95%CI，0.57~0.88]。不利基因分析显示，这13个SNP对风险的累积效应(P为Trend<；0.0001)。确定了潜在的更高级别的基因-基因相互作用，根据患者的基因特征将患者归类为不同的风险组。在临床结果研究中，24个SNPs与总生存率显著相关，17个SNPs与治疗反应显著相关。值得注意的是，在PDGFC中携带罕见的rs1425486纯合子基因型的患者与普通纯合子和杂合子携带者相比，总体生存较差[风险比(HR)=2.69；95%CI，1.67~4.33]和治疗反应差(OR=3.38；95%CI，1.39~8.19)。不利的基因分析也显示了较强的基因剂量效应，在不良基因数目较多的患者中，患者的存活率降低，治疗无反应的风险增加(P for Trend<；0.0001)。综上所述，miRNA相关基因多态性可能单独或联合影响卵巢癌的易感性和临床预后。
MicroRNAs (miRNA) play important roles in tumorigenesis. Genetic variations in miRNA processing genes and miRNA binding sites may affect the biogenesis of miRNA and the regulatory effect of miRNAs to their target genes, hence promoting tumorigenesis. This study analyzed 226 single nucleotide polymorphisms (SNP) in miRNA processing genes and miRNA binding sites in 339 ovarian cancer cases and 349 healthy controls to assess association with cancer risk, overall survival, and treatment response. Thirteen polymorphisms were found to have significant association with risk. The most significant were 2 linked SNPs (r2 = 0.99), rs2740351 and rs7813 in GEMIN4 [odds ratio (OR) = 0.71; 95% confidence interval (CI), 0.57–0.87 and OR = 0.71; 95% CI, 0.57–0.88, respectively]. Unfavorable genotype analysis showed the cumulative effect of these 13 SNPs on risk (P for trend < 0.0001). Potential higher order gene–gene interactions were identified, which categorized patients into different risk groups according to their genotypic signatures. In the clinical outcome study, 24 SNPs exhibited significant association with overall survival and 17 SNPs with treatment response. Notably, patients carrying a rare homozygous genotype of rs1425486 in PDGFC had poorer overall survival [hazard ratio (HR) = 2.69; 95% CI, 1.67–4.33] and worse treatment response (OR = 3.38; 95% CI, 1.39–8.19), compared to carriers of common homozygous and heterozygous genotypes. Unfavorable genotype analyses also showed a strong gene-dosage effect with decreased survival and increased risk of treatment nonresponse in patients with greater number of unfavorable genotypes (P for trend < 0.0001). Taken together, miRNA-related genetic polymorphisms may impact ovarian cancer predisposition and clinical outcome both individually and jointly.