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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

Circulating Tumor DNA in Melanoma: Advances in Detection, Clinical Applications, and Integration with Emerging Technologies

by
Nicole Charbel
1,†,
Joe Rizkallah
2,†,
Mark Bal
1,
Amal El Masri
1,
Elsa Armache
1,
Malak Ghezzawi
3,
Ali Awada
1,
Lara Kreidieh
1,
Jad Mehdi
1 and
Firas Kreidieh
1,*
1
Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon
2
Department of Diagnostic Radiology, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon
3
Department of Surgery, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2026, 27(3), 1569; https://doi.org/10.3390/ijms27031569
Submission received: 17 December 2025 / Revised: 30 January 2026 / Accepted: 4 February 2026 / Published: 5 February 2026
(This article belongs to the Special Issue Circulating Cell-Free Nucleic Acids and Cancers: 3rd Edition)
Versions Notes

Abstract

Circulating tumor DNA (ctDNA) has gained increasing attention as a non-invasive biomarker with potential utility across multiple stages of melanoma. ctDNA reflects tumor-derived genetic alterations in real time and has shown value in detecting minimal residual disease, identifying early recurrence, estimating tumor burden, and monitoring response to systemic therapies. In early-stage melanoma, postoperative ctDNA positivity is strongly associated with higher recurrence risk and often precedes radiologic detection. In advanced disease, ctDNA correlates with tumor volume and can distinguish responders from non-responders during targeted therapy and immunotherapy, while also identifying emerging resistance mechanisms. Despite these advantages, clinical implementation remains limited by low shedding in early-stage disease, variation among detection platforms, and the absence of standardized clinical thresholds. Recent advances, including fragmentomics, methylation assays, and multi-target sequencing strategies, aim to improve sensitivity, particularly in low-tumor-burden settings. Integration of ctDNA with radiomics, artificial intelligence, and digital pathology represents an additional opportunity to enhance precision in risk stratification and treatment adaptation. This review summarizes current evidence on ctDNA biology, detection methods, and clinical applications in melanoma and outlines ongoing challenges and future directions required for translation into routine practice.
Keywords: circulating tumor DNA; melanoma; minimal residual disease; recurrence; treatment monitoring; liquid biopsy circulating tumor DNA; melanoma; minimal residual disease; recurrence; treatment monitoring; liquid biopsy

Share and Cite

MDPI and ACS Style

Charbel, N.; Rizkallah, J.; Bal, M.; El Masri, A.; Armache, E.; Ghezzawi, M.; Awada, A.; Kreidieh, L.; Mehdi, J.; Kreidieh, F. Circulating Tumor DNA in Melanoma: Advances in Detection, Clinical Applications, and Integration with Emerging Technologies. Int. J. Mol. Sci. 2026, 27, 1569. https://doi.org/10.3390/ijms27031569

AMA Style

Charbel N, Rizkallah J, Bal M, El Masri A, Armache E, Ghezzawi M, Awada A, Kreidieh L, Mehdi J, Kreidieh F. Circulating Tumor DNA in Melanoma: Advances in Detection, Clinical Applications, and Integration with Emerging Technologies. International Journal of Molecular Sciences. 2026; 27(3):1569. https://doi.org/10.3390/ijms27031569

Chicago/Turabian Style

Charbel, Nicole, Joe Rizkallah, Mark Bal, Amal El Masri, Elsa Armache, Malak Ghezzawi, Ali Awada, Lara Kreidieh, Jad Mehdi, and Firas Kreidieh. 2026. "Circulating Tumor DNA in Melanoma: Advances in Detection, Clinical Applications, and Integration with Emerging Technologies" International Journal of Molecular Sciences 27, no. 3: 1569. https://doi.org/10.3390/ijms27031569

APA Style

Charbel, N., Rizkallah, J., Bal, M., El Masri, A., Armache, E., Ghezzawi, M., Awada, A., Kreidieh, L., Mehdi, J., & Kreidieh, F. (2026). Circulating Tumor DNA in Melanoma: Advances in Detection, Clinical Applications, and Integration with Emerging Technologies. International Journal of Molecular Sciences, 27(3), 1569. https://doi.org/10.3390/ijms27031569

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