Circular RNAs as next-generation biomarkers for minimal residual disease: Mechanistic insights and clinical
Tareq Nayef AlRamadneh1, Hussein Salim Abed2, Sarah Qutayba Badraldin Qutayba Badraldin3
1Faculty of Allied Medical Sciences, Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Jordan.
Abstract:
Minimal residual disease (MRD) denotes the persistence of malignant cells below the detection limits of conventional diagnostics and is a principal determinant of relapse and therapeutic failure. Enhancing MRD detection is therefore essential for precision oncology. Tumor-derived circular RNAs (circRNAs)-covalently closed transcripts defined by back-splice junctions-have emerged as compelling biomarkers for MRD owing to their exceptional stability, resistance to exonucleases, and enrichment in extracellular vesicles, which together enable reliable detection in biofluids. Beyond these analytical advantages, circRNAs actively participate in tumor biology through miRNA sponging, protein scaffolding, and transcriptional regulation, processes that contribute to epithelial-mesenchymal transition, therapy resistance, and metastatic competence. This review integrates current knowledge of circRNA biogenesis and molecular function, surveys cancer-type-specific circRNA expression signatures, and evaluates evidence for their utility in MRD monitoring across hematologic and solid malignancies. We propose multilayered diagnostic frameworks combining circRNA profiling with circulating tumor DNA, exosomal cargo analysis, and AI-driven bioinformatics to improve sensitivity, specificity, and longitudinal risk stratification. Finally, we critically examine translational hurdles-preanalytical standardization, assay harmonization, cross-platform reproducibility, clinical thresholding, and prospective validation-and outline strategic priorities to accelerate clinical implementation of circRNA-based MRD surveillance for personalized patient management.
Insights
Circular RNAs (circRNAs) show promise for detecting minimal residual disease (MRD) in cancer. Combining circRNA profiling with other methods can improve early cancer detection and patient management.
Area of Science:
- Biomarkers
- Molecular Oncology
- Cancer Diagnostics
Background:
- Minimal residual disease (MRD) is crucial for predicting cancer relapse and treatment failure.
- Current diagnostics have limitations in detecting MRD, necessitating improved methods for precision oncology.
- Tumor-derived circular RNAs (circRNAs) are stable, enriched in extracellular vesicles, and detectable in biofluids, making them promising MRD biomarkers.
Purpose of the Study:
- To review the biogenesis, molecular functions, and expression signatures of circRNAs in cancer.
- To evaluate the utility of circRNAs for MRD monitoring in both hematologic and solid tumors.
- To propose integrated diagnostic strategies for enhanced MRD detection and risk stratification.
Main Methods:
- Literature review integrating knowledge on circRNA biology and function.
- Survey of cancer-specific circRNA expression profiles.
- Evaluation of evidence for circRNA utility in MRD monitoring across various cancer types.
Main Results:
- CircRNAs possess unique properties (stability, enrichment) suitable for sensitive MRD detection.
- circRNAs actively regulate tumor progression, influencing EMT, therapy resistance, and metastasis.
- Multilayered diagnostic frameworks combining circRNAs with ctDNA, exosomes, and AI show potential for improved MRD surveillance.
Conclusions:
- circRNAs represent a novel class of biomarkers for MRD detection and monitoring.
- Integrated diagnostic approaches incorporating circRNAs can enhance sensitivity, specificity, and longitudinal risk stratification.
- Addressing translational hurdles is critical for implementing circRNA-based MRD surveillance in clinical practice.
