Circulating MicroRNA Biomarkers in Melanoma: Tools and Challenges in Personalised Medicine

Abstract

Effective management of melanoma depends heavily on early diagnosis. When detected in early non-metastatic stages, melanoma is almost 100% curable by surgical resection, however when detected in late metastatic stages III and IV, 5-year survival rates drop to ~50% and 10–25%, respectively, due to limited efficacy of current treatment options. This presents a pressing need to identify biomarkers that can detect patients at high risk of recurrence and progression to metastatic disease, which will allow for early intervention and survival benefit. Accumulating evidence over the past few decades has highlighted the potential use of circulating molecular biomarkers for melanoma diagnosis and prognosis, including lactate dehydrogenase (LDH), S100 calcium-binding protein B (S100B) and circulating tumor DNA (ctDNA) fragments. Since 2010, circulating microRNAs (miRNAs) have been increasingly recognised as more robust non-invasive biomarkers for melanoma due to their structural stability under the harsh conditions of the blood and different conditions of sample processing and isolation. Several pre-analytical and analytical variables challenge the accurate quantification of relative miRNA levels between serum samples or plasma samples, leading to conflicting findings between studies on circulating miRNA biomarkers for melanoma. In this review, we provide a critical summary of the circulating miRNA biomarkers for melanoma published to date.

Extracellular Vesicles and Epigenetic Modifications Are Hallmarks of Melanoma Progression

“…The liquid biopsy is emerging as a helpful alternative to conventional tissue biopsy, which provides a non-invasive approach for the detection and real-time measuring of cancer biomarkers by simple drown of blood procedures as well as other biological fluids including urine, saliva, or ascites [101]. In this context, increased levels of exosomal miR-17, miR-19a, miR-21, miR-126, and miR-149 were measured in the plasma of patients with sporadic metastatic melanoma as compared to a healthy control and proposed as possible biomarkers in the clinical setting [102,103].…”

miRNAs as Key Players in the Management of Cutaneous Melanoma

“…Like other extracellular vesicles, exosomes contain proteins, RNA, miRNA, DNA, and lipids [88] that are delivered to the intercellular environment playing a pivotal role in cell-cell communication. Loading of circulating miRNAs into exosomes prevents degradation by serum and plasma RNases [89,90]. As such, circulating miRNAs are very stable under the harsh conditions of the blood [91], a feature that points to their potential use as easily accessible markers to help clinicians monitor cutaneous melanoma progression and treatment response [92].Since 2010, numerous efforts have been made to prove that circulating miRNAs are useful as melanoma diagnostic biomarkers.…”

Clinical Relevance of Liquid Biopsy in Melanoma and Merkel Cell Carcinoma

“…Several reviews have highlighted the role of miRNAs as potential diagnostic and prognostic biomarkers and as key molecular regulators in melanoma development [101][102][103]. For example, miR-137 is a well-established tumor suppressor miRNA often downregulated in melanoma and in many other cancer types.…”

“…Tumor-derived exosomes may also modulate the immune cell behavior, by dampening the anti-tumor immune response and promoting melanoma progression [109]. Conversely, exosomes secreted by immune cells may modulate melanoma cell behavior and exert therapeutic effects [103,110].…”