microRNA Profiles in Stage I Clear Cell Renal Cell Carcinoma Predicts Progression to Metastatic Disease
Matthew J. Moynihan, MD, MPH; Travis Sullivan, MS, Jared Schober, MD; Marc Calabrese, MD; Ariel Fredrick, MD; Eric Burks, MD; David Canes, MD; Kimberly Rieger-Christ, PhD
Lahey Clinic, Burlington, MA
BACKGROUND: Despite surgical intervention, patients with small localized clear cell renal cell carcinoma (ccRCC) can still develop metastatic disease. MicroRNAs (miRNA) are small non-coding RNAs regulating gene expression that have shown to be early oncologic diagnostic biomarkers and potential therapeutic targets. Recent research has focused on a subset of miRNA, termed metastamirs, that are thought to play a role in various steps of tumor metastasis. This investigation sought to identify miRNA profiles of small, pathologically confirmed ccRCC tumors that could predict metachronous metastatic disease.
METHODS: Samples of pathologic stage 1 ccRCC tumors (<5cm) from two institutions were studied in two stages: initial miRNA screening, followed by a validation study. All specimens were secondarily reviewed by a single pathologist to confirm their characteristics and patient data was collected in a retrospective manner after IRB approval. For the screening phase 752 miRNA were evaluated on each sample to identify those with differential expression between tumors that did (n=10) or did not (n=10) progress to metachronous metastatic disease. In the second phase, 54 additional samples from two institutions (29 non-progressors, 25 with progression to metachronous metastasis) were utilized in a validation analysis. This analysis investigated 20 miRNA in each specimen to determine if a miRNA panel could differentiate an aggressive natural history.
RESULTS: In the screening analysis, 27 miRNA were found to be significantly differentially expressed (p<0.05, FDR<0.1) between the groups. In the validation phase, 14 of the 20 miRNA examined were confirmed to have differential expression. Two of these miRNA biomarkers, miR-140-3p and miR-26a-5p, were found to differentiate between localized and progressive disease showing a sensitivity of 80% and 64%, specificity of 79.3% and 86.2%, respectively. MiR-10a-5p, -10b-5p, and -21-5p were also significantly differentially expressed between groups, and supports previous ccRCC investigations regarding miRNA phenotypes and oncologic aggressiveness.
CONCLUSIONS: This investigation identified miRNA biomarkers among ccRCC samples that may differentiate between localized tumors and those that progress to metastatic disease in this group of stage I tumors. The miRNA profiles determined in this study have the potential to identify patients with small renal masses who are likely to have progressive ccRCC.
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