Circulating Cell-Free miR-375 as Surrogate Marker of Tumor Burden in Merkel Cell Carcinoma

• Published in: Clinical cancer research 2018-12, Vol.24 (23), p.5873-5882
• Main Authors: Fan, Kaiji, Ritter, Cathrin, Nghiem, Paul, Blom, Astrid, Verhaegen, Monique E, Dlugosz, Andrzej, Ødum, Niels, Woetmann, Anders, Tothill, Richard W, Hicks, Rodney J, Sand, Michael, Schrama, David, Schadendorf, Dirk, Ugurel, Selma, Becker, Jürgen C
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers, Tumor; Carcinoma, Merkel Cell - blood; Carcinoma, Merkel Cell - diagnosis; Carcinoma, Merkel Cell - genetics; Case-Control Studies; Cell Line, Tumor; Chick Embryo; Circulating MicroRNA; Female; Gene Expression Regulation, Neoplastic; Humans; Male; MicroRNAs - genetics; Positron Emission Tomography Computed Tomography; Prognosis; Real-Time Polymerase Chain Reaction; ROC Curve; Tumor Burden; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-18-1184

Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden; circulating cell-free miRNA may serve this purpose. Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of 2 preclinical MCC models, and sera of 109 patients with MCC and 30 healthy controls by nCounter human-v2-miRNA expression or miR-375-specific real-time PCR assays. The patients' sera consisted of two retrospective (discovery and training) and two prospective (validation) cohorts. miR-375 expression was high in MCC cell lines and tissues compared with non-MCCs. It was readily detected in MCC-conditioned medium and sera of preclinical models bearing MCC xenografts. miR-375 levels were higher in sera from tumor-bearing patients with MCC than in tumor-free patients or healthy controls ( < 0.0005). Moreover, miR-375 serum levels correlated with tumor stage in tumor-bearing ( = 0.037) but not in tumor-free ( = 0.372) patients with MCC. miR-375 serum level showed high diagnostic accuracy to discriminate tumor-bearing and tumor-free patients with MCC as demonstrated by ROC curve analysis in the retrospective cohorts (AUC = 0.954 and 0.800) as well as in the prospective cohorts (AUC = 0.929 and 0.959). miR-375 serum level reflected dynamic changes in tumor burden of patients with MCC during therapeutic interventions. Circulating cell-free miR-375 proved as a surrogate marker for tumor burden in MCC without restriction to polyomavirus positivity; it thus appears to be useful for therapy monitoring and the follow-up of patients with MCC.