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MicroRNA Expression Profile Predictive of High Grade Non-Invasive Urothelial Cancer Progression
Sara M. Lenherr, M.D., Sheaumei Tsai, M.D., Cara B. Cimmino, M.D., Kimberly M. Rieger-Christ, Ph.D., John A. Libertino, M.D., Ian C. Summerhayes, Ph.D..
Lahey Clinic Medical Center, Burlington, MA, USA.

BACKGROUND: MicroRNA (miRNA) has been shown to play a role in different malignancies regulating the expression of genes involved in tumor suppression and oncogenesis. Several studies have reported differential expression of miRNA between normal and tumor tissue and recent investigations have identified miRNA protein targets involved in tumorigenesis.
High grade, superficial urothelial cancer (UC) has a 25-40% risk of progression to muscle invasive disease. Predicting those cancers destined to progress based on expression profiling would be clinically useful. In this study we sought to identify a panel of miRNAs differentially expressed in stable high-grade superficial UC compared to pathologically identical lesions progressing to muscle invasion.
METHODS: After Institutional Review Board approval was obtained, high-grade superficial UC were identified and total RNA was extracted from paraffin embedded tissue using the RecoverAll™ Total Nucleic Acid Isolation kit. Patients were categorized into two groups: non-progressors (superficial UC with at least 3 years follow-up) or progressors (advancing to ≥T2). Patients with previous tumors of the upper tract (RCC or UC), prior systemic chemotherapy, or previous pelvic irradiation were excluded. Information on prior intravesical therapy and the presence of CIS was recorded. Total RNA was pooled for microarray analysis of the two groups. Microarray data was analyzed using the LOWESS normalization method. Selected miRNAs were verified with qRT-PCR on an expanded group of tumor specimens. Student’s t-test analysis was performed to identify miRNAs predictive of tumor progression.
RESULTS: Using microarray analysis, we identified a unique panel of 193 miRNAs with potential involvement in the progressive phenotype of high-grade superficial UC. Eighty of these miRNAs were upregulated, and 113 were downregulated in progressor versus non-progressor patient samples. To date, differential expression of 35 miRNAs has been validated with qRT-PCR on 71 paraffin embedded samples (54 non-progressor, 17 progressor). Two miRNAs have demonstrated significantly decreased expression (p≤0.05) in the progressor group while several others show notable changes and are presently under further investigation.
CONCLUSIONS: In this study, we have identified a panel of miRNAs that can differentiate high-grade superficial UC that progress to muscle invasion compared to those that remain superficial. Further validation studies are underway to investigate additional miRNAs and determine the mechanism by which these miRNAs promote tumor invasion and progression. For these challenging tumors, miRNA profiling has the potential to allow early cystectomy in those patients destined to fail intravesical therapy and prolonged surveillance.


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