Prognostic and diagnostic values of non-coding RNAs as biomarkers for breast cancer: An umbrella review and pan-cancer analysis
Authors: Bahramy Afshin , Zafari Narges , Rajabi Fatemeh , Aghakhani Amirhossein , Jayedi Ahmad , Khaboushan Alireza Soltani , Zolbin Masoumeh Majidi , Yekaninejad Mir Saeed 
Published: January 2023

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.