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Evaluation of Genetic Variants in MicroRNA-Related Genes and Risk of Bladder Cancer

Departments of ¹ Epidemiology and ² Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ³ School of Public Health, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Xifeng Wu, Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-2485; Fax: 713-792-4657; E-mail: xwu{at}mdanderson.org.

Key Words: microRNA • polymorphism • bladder cancer

MicroRNAs (miRNA) are small noncoding RNA molecules involved in a diversity of cellular functions. Although it has been reported that global suppression of the miRNA biogenesis pathway leads to enhanced tumorigenesis, the effect of common genetic variants of miRNA-related genes on cancer predisposition is unclear. To better understand this effect, we genotyped 41 single-nucleotide polymorphisms (SNP) from 24 miRNA-related genes in a case-control study conducted in 746 Caucasian patients with bladder cancer and 746 matched controls. The homozygous variant genotype of a nonsynonymous SNP in the GEMIN3 gene (rs197414) was associated with a significantly increased bladder cancer risk [odds ratios (OR), 2.40; 95% confidence interval (95% CI), 1.04–5.56]. Several additional miRNA-related SNPs were also identified that showed a borderline significant association with bladder cancer risk. Haplotype analysis indicated that a common haplotype of the GEMIN4 gene was associated with a significantly increased bladder cancer risk with an OR of 1.25 (95% CI, 1.01–1.54). To assess the aggregate effects of the promising SNPs, we performed a combined unfavorable genotype analysis that included all SNPs showing at least a borderline statistical significance. We found that, compared with the low-risk reference group with less than two unfavorable genotypes, the medium-risk group with two unfavorable genotypes exhibited a 1.29-fold (0.92–1.81) increased risk whereas the high-risk group with more than two unfavorable genotypes exhibited a 1.92-fold (1.36–2.71) increased risk (P_trend < 0.0001). Overall, this is the first epidemiologic study showing that miRNA-related genetic variants may affect bladder cancer risk individually and jointly. [Cancer Res 2008;68(7):2530–7]