S. Y. Kim1, T. Kawaguchi1, L. Yan2, Q. Qi2, S. Liu2, J. Young1, K. Takabe1 1Roswell Park Cancer Institute,Surgical Oncology,Buffalo, NY, USA 2Roswell Park Cancer Institute,Biostatistics And Bioinformatics,Buffalo, NY, USA
Introduction: MicroRNAs (miRNAs) are noncoding RNAs with 19-25 nucleotides that exert their genetic effect by either mRNA degradation or inhibition of the translation of mRNA. Dysregulations of miRNAs have been identified to play a critical role in carcinogenesis and the development of various types of cancer including breast cancer (BrCa). Some miRNAs are reported as oncogenic miRNAs that are associated with drug resistance in BrCa patients. Some miRNAs, such as miR-18a and miR-205, are reported to have both oncogenic and suppressive roles. MiR-744, on the other hand, has been reported to promote cell proliferation in vitro, but its relevance in patients is unknown. Identification of novel prognostic biomarkers typically requires a big dataset that provides sufficient statistical power for discovery and validation research. In this study we took advantage of the high-throughput data from The Cancer Genome Atlas (TCGA) as a validation cohort to evaluate the clinical relevance of miR-18a, miR-21, miR-155, miR-205,and miR-744.
Methods: All data was obtained from The Cancer Genome Atlas (TCGA). Expression of four miRNAs, miR-18a, miR-21, miR-155, and miR-205, which have oncogenic and/or suppressive roles in BrCa patients, and another miRNA with unknown clinical relevance (miR-744) were retrieved from the GDC data portal for analyses. After miRNA-specific thresholds were derived from the data and used to group the patients into either a high expression or low expression group, survival data was calculated using the Cox proportional hazard model.
Results: Among the 1097 breast cancer samples logged in TCGA, 1053 samples were found to contain both clinical data and microRNA-seq datasets on the miRNAs of interest. High expression of miR-18a, the miRNA that is reported to have both oncogenic and suppressive roles in BrCa patients, demonstrated significantly better prognosis (p=0.037), whereas it was not significant with miR-205 expression (p=0.070). Surprisingly, high expression levels of miR-21 and miR-155, the two miRNAs that are well known as “oncogenic” miRNAs, also demonstrated significantly better prognoses (p=0.030 and 0.005, respectively). MiR-744, which currently has unknown clinical relevance, but has been reported to be oncogenic in vitro, was also associated with a significantly better prognosis when highly expressed (p=0.027).
Conclusion: By utilizing a big dataset (TCGA) with sufficient statistical power, we found that high expression of miR-18a, miR-21, miR-155, and miR-744 were all significantly associated with better overall survival. We were able to clarify that miR-18a and miR-205 had a positive impact on survival despite some reports of their oncogenic functions. We conclude that it is necessary to reevaluate the survival impact of each miRNA whose functions are seemingly straightforward.