Prognostic potential of microRNA-encoding gene signatures in gynecologic cancers

Background/Significance: Effective early-stage biomarkers are needed for improving outcomes in gynecologic cancers. Micro RNAs (miRNAs) are small non-coding RNAs that function in post-transcriptional gene regulation and their dysfunction can play key role in cancer development and progression. Recently, the role of miRNAs is gaining attention as circulating biomarkers for various malignancies. However, there is a gap in studies involving gynecologic cancers with high-mortality rates such as ovarian serous cystadenocarcinoma (OV), uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS). The objectives of this study are to analyze the expression profiles of selected miRNA-coding genes such as hsa-mir-6511b-1, hsa-mir-6820, and hsa-mir-3198-2 in tumor specimens from patients with OV, UCEC, and UCS cancers using The Cancer Genome Atlas (TCGA) datasets. Additionally, we evaluated the prognostic significance of these miRNAs by correlating their expression levels with overall survival and clinical outcomes. Methods: Data were obtained from TCGA, an online portal for analyzing tumor genes and survival curves. A comparison was made between the common miRNA-coding genes in OV vs UCS, OV vs UCEC, and UCS vs UCEC. Survival curves were obtained for OV (n=474) vs UCS (n=56). Clinical trials information was accessed through clinicaltrials.gov. Data was analyzed and the statistical significance was assessed by Student's t-test (comparisons between two-groups), or one-way ANOVA (for multiple-groups), and survival curves were analyzed using Kaplan-Meier method with log-rank test. A p-value of 0.05 or less was considered significant. Results: Analyses revealed differences in patient survival based on the expression of the miRNA-coding genes of interest, hsa-mir-6511b-1, hsa-mir-6820, and hsa-mir-3198-2, in OV and UCS. High expression of hsa-mir-6511b-1 was associated with a shorter survival period in both OV (p=0.021) and UCS (p=0.035) patients. In contrast, high expression of hsa-mir-6820 showed opposite effects: it was linked to shorter survival in OV patients (p=0.024) but longer survival in UCS patients (p=0.028). High expression of hsa-mir-3198-2 was associated with longer survival in both OV (p=0.027) and UCS (p=0.046) patients. Data suggest that the role of miRNAs in these gynecologic cancers appears to be complex, showing both oncogenic and protective effects. Conclusions: These preliminary findings emphasize that miRNAs behave in a context-dependent manner in gynecologic cancers. Importance of miRNAs should be further studied to validate their potential as biomarkers for early detection, prognosis, and treatment strategies. Our laboratory is conducting translational studies to precisely understand the role of miRNA-coding genes on drug resistance to address platinum-resistance in gynecologic cancer models.