Abstract
MicroRNAs (miRNAs) are implicated in the development of nearly all cancers and may function as promising biomarkers for early detection, diagnosis and prognosis. We sought to investigate the role of serum miRNAs as potential diagnostic biomarkers or biomarkers of risk for early-stage bladder cancer. First, we profiled global serum miRNAs in a pilot set of 10 non-muscle invasive bladder cancer (NMIBC) cases and 10 healthy controls matched on age, gender and smoking status. Eighty nine stably detectable miRNAs were selected for further testing and quantification by high-throughput Taqman analysis using the Fluidigm BioMark HD System to assess their association with NMIBC risk in both discovery and validation sets totaling 280 cases and 278 controls. We found miR-409-3p and six miRNAs expression ratios were significantly associated with risk of bladder cancer in both discovery and validation sets. Interestingly, we identified expression of miR-409-3p and miR-342-3p inversely correlated with age and age of onset of NMIBC. A risk score was generated based on the combination of three miRNA ratios (miR-29a-3p/miR-222-3p, miR-150-5p/miR-331-3p, miR-409-3p/miR-423-5p). In dichotomized analysis, we found individuals with high risk score showed increased risk of bladder cancer in the discovery, validation, and combined sets. Pathway enrichment analyses suggested altered miRNAs and cognate target genes are linked to the retinoid acid receptor (RAR) signaling pathway. Overall, these results suggested specific serum miRNA signatures may serve as noninvasive predictors of NMIBC risk. Biological insights underlying bladder cancer development based on the pathway enrichment analysis may reveal novel therapeutic targets for personalized medicine.
Highlights
Bladder cancer is the second most common genitourinary malignancy worldwide
These results suggested specific serum miRNA signatures may serve as noninvasive predictors of non-muscle invasive bladder cancer (NMIBC) risk
When the same cutoffs were applied to the validation set, one miRNA, miR-4093p, remained significantly associated with NMIBC with a significant trend for increased risk in the tertiles with reduced expression for both discovery set (P for trend = 0.013) and validation set (P for trend = 0.019) (Table 2)
Summary
Bladder cancer is the second most common genitourinary malignancy worldwide. In the United States, bladder cancer is the fourth most common cancer in men. Non-muscle invasive bladder cancer (NMIBC), including stage Ta and T1 and carcinoma in situ (CIS), accounts for 70%–80% of all newly diagnosed bladder cancer cases [2]. Cystoscopy is an uncomfortable and costly invasive procedure, while the sensitivity of urine cytology for the detection of early-stage tumors is low as there are typically few cells found in urine [4]. Extensive research has attempted to identify early detection biomarkers, but these assays are either limited with high false positive rate or low sensitivity [5]. These limitations underscore www.oncotarget.com the need for novel biomarkers, noninvasive biomarkers in serum or plasma, for early detection or diagnosis of bladder cancer
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