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. 2023 Jan 16:10:1096524.
doi: 10.3389/fmolb.2023.1096524. eCollection 2023.

Prognostic and diagnostic values of non-coding RNAs as biomarkers for breast cancer: An umbrella review and pan-cancer analysis

Affiliations

Prognostic and diagnostic values of non-coding RNAs as biomarkers for breast cancer: An umbrella review and pan-cancer analysis

Afshin Bahramy et al. Front Mol Biosci. .

Abstract

Background: Breast cancer (BC) is the most common cancer in women. The incidence and morbidity of BC are expected to rise rapidly. The stage at which BC is diagnosed has a significant impact on clinical outcomes. When detected early, an overall 5-year survival rate of up to 90% is possible. Although numerous studies have been conducted to assess the prognostic and diagnostic values of non-coding RNAs (ncRNAs) in breast cancer, their overall potential remains unclear. In this field of study, there are various systematic reviews and meta-analysis studies that report volumes of data. In this study, we tried to collect all these systematic reviews and meta-analysis studies in order to re-analyze their data without any restriction to breast cancer or non-coding RNA type, to make it as comprehensive as possible. Methods: Three databases, namely, PubMed, Scopus, and Web of Science (WoS), were searched to find any relevant meta-analysis studies. After thoroughly searching, the screening of titles, abstracts, and full-text and the quality of all included studies were assessed using the AMSTAR tool. All the required data including hazard ratios (HRs), sensitivity (SENS), and specificity (SPEC) were extracted for further analysis, and all analyses were carried out using Stata. Results: In the prognostic part, our initial search of three databases produced 10,548 articles, of which 58 studies were included in the current study. We assessed the correlation of non-coding RNA (ncRNA) expression with different survival outcomes in breast cancer patients: overall survival (OS) (HR = 1.521), disease-free survival (DFS) (HR = 1.33), recurrence-free survival (RFS) (HR = 1.66), progression-free survival (PFS) (HR = 1.71), metastasis-free survival (MFS) (HR = 0.90), and disease-specific survival (DSS) (HR = 0.37). After eliminating low-quality studies, the results did not change significantly. In the diagnostic part, 22 articles and 30 datasets were retrieved from 8,453 articles. The quality of all studies was determined. The bivariate and random-effects models were used to assess the diagnostic value of ncRNAs. The overall area under the curve (AUC) of ncRNAs in differentiated patients is 0.88 (SENS: 80% and SPEC: 82%). There was no difference in the potential of single and combined ncRNAs in differentiated BC patients. However, the overall potential of microRNAs (miRNAs) is higher than that of long non-coding RNAs (lncRNAs). No evidence of publication bias was found in the current study. Nine miRNAs, four lncRNAs, and five gene targets showed significant OS and RFS between normal and cancer patients based on pan-cancer data analysis, demonstrating their potential prognostic value. Conclusion: The present umbrella review showed that ncRNAs, including lncRNAs and miRNAs, can be used as prognostic and diagnostic biomarkers for breast cancer patients, regardless of the sample sources, ethnicity of patients, and subtype of breast cancer.

Keywords: breast cancer; non-coding RNAs; non-invasive tool; pan-cancer analysis; prognostic and diagnostic.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) Bivariate boxplot indicated the dispersion of datasets as an indicator of heterogeneity. (B) Summary receiver operator characteristic (SROC) curves. AUC, area under the curve; SENS, sensitivity; and SPEC, specificity. (C) Conditional plot: the overall results for NPV, PPV, LR+, and LR. According to the bivariate boxplot, significant heterogeneity was observed among studies. I2 values of heterogeneity analysis resulted in 97.33 for sensitivity and 88.64 for specificity, which showed significant heterogeneity. The SROC curve showed that the values of sensitivity and specificity were 0.80 and 0.82, respectively.
FIGURE 2
FIGURE 2
Forest plots of the sensitivity and specificity of the ncRNA assays. The overall results for negative predictive value (NPV), positive predictive value (PPV), PLR+, PLR, sensitivity, and specificity were 0.79, 0.80, 4.44, 0.25, 0.80, and 0.82, respectively.
FIGURE 3
FIGURE 3
Golf diagram of (A) goodness-of-fit, (B) bivariate normality, (C) influence analysis, and (D) outlier detection. The bivariate random-effects model’s suitability is confirmed by plotting the goodness-of-fit and bivariate normality. Influence analysis revealed that datasets numbered 2, 11, 22, and 25 that belong to the let-7 family, MALAT1, miR-34a, and precursor miR-203a had Cook’s distances greater than 0.75 and were the most influential. Datasets numbered 2, 11, and 25 (related to the let-7 family, MALAT1, and precursor miR-203a, respectively) were detected as outliers, potentially accounting for some of the heterogeneity that we observed.
FIGURE 4
FIGURE 4
Gene Ontology and pathway analysis. Venn diagram shows the common genes that are targeted by miRNAs in this study. (A) Sankey diagram that shows the network between mRNA-miRNA-lncRNA. (B) GO enrichment analysis reveals BB, CC, and MF for target genes of lncRNAs. (C) Circos plot depicts the Q28 pathways in which these genes are involved (D).
FIGURE 5
FIGURE 5
Expression of target genes of studied miRNAs in pan-cancer data.
FIGURE 6
FIGURE 6
Kaplan–Meier survival analysis, OS, and RFS for mRNAs. It showed that increased expression of E2F3 (HR = 1.41), IRAK1 (HR = 1.58), and UBR5 (HR = 1.72) indicated poor OS prognosis, while decreased expression of BTG2 (HR = 0.53) is an indicator of poor OS. RFS analysis revealed that higher expression levels of E2F3 (HR = 1.82) and IRAK1 (HR = 1.81) are associated with poor RFS prognosis. Lower expression levels of BTG2 (HR = 0.50) and SMAD4 (HR = 0.63) are associated with poor RFS prognosis in patients.

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References

    1. Adhami M., Haghdoost A. A., Sadeghi B., Malekpour Afshar R. (2018). Candidate miRNAs in human breast cancer biomarkers: A systematic review. Breast Cancer 25 (2), 198–205. 10.1007/s12282-017-0814-8 - DOI - PubMed
    1. Alyami N. M. (2021). MicroRNAs role in breast cancer: Theranostic application in Saudi arabia. Front. Oncol. 11, 717759. 10.3389/fonc.2021.717759 - DOI - PMC - PubMed
    1. Anwar S. L., Sari D. N. I., Kartika A. I., Fitria M. S., Tanjung D. S., Rakhmina D., et al. (2019). Upregulation of circulating MiR-21 expression as a potential biomarker for therapeutic monitoring and clinical outcome in breast cancer. Asian Pac. J. Cancer Prev. APJCP 20 (4), 1223–1228. 10.31557/APJCP.2019.20.4.1223 - DOI - PMC - PubMed
    1. Arisan E. D., Rencuzogullari O., Cieza-Borrella C., Miralles Arenas F., Dwek M., Lange S., et al. (2021). MiR-21 is required for the epithelial–mesenchymal transition in MDA-MB-231 breast cancer cells. Int. J. Mol. Sci. 22 (4), 1557. 10.3390/ijms22041557 - DOI - PMC - PubMed
    1. Bahramy A., Zafari N., Izadi P., Soleymani F., Kavousi S., Noruzinia M. (2021). The role of miRNAs 340-5p, 92a-3p, and 381-3p in patients with endometriosis: A plasma and mesenchymal stem-like cell study. BioMed Res. Int. 2021, 5298006. 10.1155/2021/5298006 - DOI - PMC - PubMed

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