Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Carcinogenesis. 2013 May;34(5):1006-11. doi: 10.1093/carcin/bgt006. Epub 2013 Jan 14.
Micro-RNAs (miRNAs) are small non-coding RNA molecules, which can act as either oncogenes or tumor suppressors. Dysregulated expression of miRNA genes have been implicated in the development of many different cancers. We hypothesize that genetic variations in miRNA biogenesis genes may be associated with the prognosis of bladder cancer. We genotyped 76 single nucleotide polymorphisms (SNPs) in eight miRNA biogenesis genes in 421 patients with non-muscle-invasive bladder cancer (NMIBC). We analyzed the associations of SNPs with recurrence and progression in all patients as well as stratified by treatment: transurethral resection (TUR) alone or TUR plus intravesical bacillus Calmette-Guérin (BCG) instillation. Two SNPs were significantly associated with tumor recurrence in TUR only subgroup after adjustment for multiple comparisons (Q < 0.1). The most significant SNP was rs197412 in DDX20: the variant allele conferred a decreased risk of recurrence [hazard ratio (HR) = 0.58, 95% confidence interval (95% CI) = 0.40-0.82]. This SNP was validated in a separate group of 586 NMIBC patients and the pooled HR was 0.62 (95% CI = 0.48-0.81, P < 0.001). Two linked SNPs (rs2073778 and rs720012) in DGCR8 showed significant association with tumor progression (HR = 4.00, 95% CI = 1.53-10.46, P = 0.005). A strong gene-dosage effect was observed with higher risk for tumor recurrence and progression with increasing number of unfavorable genotypes. Haplotype and survival tree analyses further characterized the association of miRNA-related SNPs with tumor recurrence and progression. Taken together, our results indicate that genetic variants in miRNA biogenesis pathway may influence bladder cancer clinical outcome in NMIBC patients.
微小 RNA（miRNA）是一种小的非编码 RNA 分子，可作为癌基因或肿瘤抑制因子。miRNA 基因表达失调与许多不同癌症的发生有关。我们假设 miRNA 生物发生基因的遗传变异可能与膀胱癌的预后有关。我们在 421 例非肌层浸润性膀胱癌（NMIBC）患者中对 8 个 miRNA 生物发生基因中的 76 个单核苷酸多态性（SNP）进行了基因分型。我们分析了所有患者以及根据治疗分层（单纯经尿道切除术（TUR）或 TUR 联合膀胱内卡介苗（BCG）灌注）的 SNP 与复发和进展的相关性。在调整了多次比较的 Q 值（<0.1）后，两个 SNP 与 TUR 仅亚组的肿瘤复发显著相关。最显著的 SNP 是 DDX20 中的 rs197412：变异等位基因降低了复发的风险[风险比（HR）=0.58，95%置信区间（95%CI）=0.40-0.82]。在另一组 586 例 NMIBC 患者中验证了该 SNP，合并 HR 为 0.62（95%CI=0.48-0.81，P<0.001）。DGCR8 中的两个连锁 SNP（rs2073778 和 rs720012）与肿瘤进展显著相关（HR=4.00，95%CI=1.53-10.46，P=0.005）。观察到强烈的基因剂量效应，随着不利基因型数量的增加，肿瘤复发和进展的风险增加。单倍型和生存树分析进一步说明了 miRNA 相关 SNP 与肿瘤复发和进展的相关性。总之，我们的研究结果表明，miRNA 生物发生途径中的遗传变异可能影响 NMIBC 患者的膀胱癌临床结局。
