Dottorato in MEDICINA MOLECOLARE

Titolo della tesi: A novel microRNA signature for the detection of melanoma by liquid biopsy

Advanced stages of melanoma, characterized by metastatic processes, are associated with high mortality and morbidity, mainly due to rapid dissemination of the disease and the heterogeneous and not durable responses to current therapies. Diagnosis, patient stratification and monitoring are clinical needs that could be addressed by the identification of disease onset and relapse biomarkers. Indeed, research for more reliable non-invasive biomarkers in metastatic melanoma is still underway. MicroRNAs, small non-coding RNAs involved in gene regulation, are emerging as effective tools for diagnosis and monitoring of patients with cancer diseases. Here, we aimed to identify a melanoma-specific circulating microRNA signature and assess its value as a diagnostic tool. The study design consisted of one discovery and two validation phases. In the discovery phase, circulating plasma extracellular vesicles (pEV) associated microRNAs profiles were obtained from a discovery cohort of metastatic melanoma patients and normal subjects, used as controls. A pEV-microRNA signature was obtained using a LASSO penalized logistic regression model. The pEV-microRNA signature was subsequently validated both in a publicly available dataset and in an independent internal cohort. A melanoma-specific circulating microRNAs panel was thus identified and validated in three independent cohorts that presented high accuracy in differentiating melanoma patients from healthy subjects, and ROC analysis showed high specificity and sensitivity, with an area under the curve (AUC) of 1.00. Investigation of the function of the pEV-microRNA signature evidenced their possible immune suppressive role in melanoma patients. The results of this study demonstrate that a blood test based on circulating microRNAs can non-invasively detect melanoma, offering a novel diagnostic tool for improving standard care. Moreover, an immune suppressive role for melanoma pEV-microRNAs was revealed.