Genetic variations in microRNA-biogenesis genes and clinical outcomes in non-muscle invasive bladder cancer
Ke HL, Chen M, Ye Y, Hildebrandt MA, Wu WJ, Wei H, Huang M, Chang DW, Dinney CP, Wu X. Carcinogenesis. 2013 Jan 14. [Epub ahead of print]


Departments of Epidemiology The University of Texas MD Anderson Cancer Center, Houston, Texas.


MicroRNAs (miRNAs) are small noncoding 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 and treatment response. We genotyped 76 single nucleotide polymorphisms (SNPs) in eight miRNA biogenesis 421 patients with non-muscle invasive bladder cancer (NMIBC). For validation, some of the top SNPs were genotyped in a separate group of 586 NMIBC patients. Most of these patients were treated with trans-urethral resection alone (TUR) or both TUR and intra-vesical Bacillus Calmette-Guérin instillation (BCG). We identified two SNPs significantly associated with cancer recurrence in TUR only treated subgroup after adjustment for multiple comparisons (q<0.1). The most significant variant was rs197412 in DDX20, whose variant conferred a decreased risk of recurrence in both the discovery (HR=0.58, 95% CI, 0.40-0.82) and validation groups (HR=0.71, 95% CI, 0.47-1.05) (Pooled HR=062, P<0.001). Two SNPs (rs2073778 and rs720012), which are linked in DGCR8, showed significant association with cancer progression with four-fold increase in risk (P=0.005). A strong gene-dosage effect was observed with higher risk for cancer recurrence and progression with increasing number of unfavorable genotypes. Haplotype and survival tree analyses further characterized the association of miRNA-related genes with cancer recurrence and progression. Taken together, our results indicate that genetic variants in miRNA biogenesis pathway may influence bladder cancer clinical outcome in TUR and BCG treated patients.