Genomic instability-derived plasma extracellular vesicle-microRNA signature as a minimally invasive predictor of risk and unfavorable prognosis in breast cancer

Abstract

Background Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer-associated deaths in women. Recent studies have indicated that microRNA (miRNA) regulation in genomic instability (GI) is associated with disease risk and clinical outcome. Herein, we aimed to identify the GI-derived miRNA signature in extracellular vesicles (EVs) as a minimally invasive biomarker for early diagnosis and prognostic risk stratification. Experimental design Integrative analysis of miRNA expression and somatic mutation profiles was performed to identify GI-associated miRNAs. Then, we constructed a discovery and validation study with multicenter prospective cohorts. The GI-derived miRNA signature (miGISig) was developed in the TCGA discovery cohort (n = 261), and was subsequently independently validated in internal TCGA validation (n = 261) and GSE22220 (n = 210) cohorts for prognosis prediction, and in GSE73002 (n = 3966), GSE41922 (n = 54), and in-house clinical exosome (n = 30) cohorts for diagnostic performance. Results We identified a GI-derived three miRNA signature (MIR421, MIR128-1 and MIR128-2) in the serum extracellular vesicles of BC patients, which was significantly associated with poor prognosis in all the cohorts tested and remained as an independent prognostic factor using multivariate analyses. When integrated with the clinical characteristics, the composite miRNA-clinical prognostic indicator showed improved prognostic performance. The miGISig also showed high accuracy in differentiating BC from healthy controls with the area under the receiver operating characteristics curve (ROC) with 0.915, 0.794 and 0.772 in GSE73002, GSE41922 and TCGA cohorts, respectively. Furthermore, circulating EVs from BC patients in the in-house cohort harbored elevated levels of miGISig, with effective diagnostic accuracy. Conclusions We report a novel GI-derived three miRNA signature in EVs, as an excellent minimally invasive biomarker for the early diagnosis and unfavorable prognosis in BC.

Circulating exosomalmiR‐363‐5pinhibits lymph node metastasis by downregulatingPDGFBand serves as a potential noninvasive biomarker for breast cancer

“…growing evidence suggesting the potential role of exosomal miRNAs in the early detection of cancer metastasis (An et al, 2015;Bao et al, 2021;Feng et al, 2019;Zhang et al, 2017). However, the relation between tumor-derived exosomal miRNAs and the lymph node metastases in breast cancer is still unclear.…”

Development and Interpretation of a Genomic Instability Derived lncRNAs Based Risk Signature as a Predictor of Prognosis for Clear Cell Renal Cell Carcinoma Patients

“…GI is a major cause of tumor heterogeneity within and between tumors (5). Moreover, it is broadly recognized that GI is closely related with the progression and prognosis of tumors (6)(7)(8)(9).…”

Regulatory Network Analysis of Mutated Genes Based on Multi-Omics Data Reveals the Exclusive Features in Tumor Immune Microenvironment Between Left-Sided and Right-Sided Colon Cancer

“…The regulatory network in biology is exceedingly complex as any alterations in gene expression could be initiated or influenced by multiple regulators such as transcription factors, miRNAs, etc. MiRNA is a kind of ncRNA that modulates the expression levels of up to 60% of the protein-coding genes at both the transcription and post-transcription level ( 31 , 32 ). So, the associations of TMG-DEG relationships identified above may be indirect and connected through miRNAs.…”