Circulating cell-free miR-375 as surrogate marker of tumor burden in Merkel cell carcinoma

July 30, 2018


Clinical Cancer Research

Publication Date

July 30, 2018


Fan K, Ritter C, Nghiem P, Blom A, Verhaegen ME, Dlugosz A, Odum N, Woetmann A, Tothill RW, Hicks RJ, Sand M, Schrama D, Schadendorf D, Ugurel S, Becker JC


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 micro(mi)RNA 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 two preclinical MCC models, sera of 109 MCC patients 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 to 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 MCC patients than in tumor-free patients or healthy controls (p<0.0005). Moreover, miR-375 serum levels correlated with tumor stage in tumor-bearing (p=0.037) but not in tumor-free (p=0.372) MCC patients. miR-375 serum level showed high diagnostic accuracy to discriminate tumor-bearing and tumor-free MCC patients as demonstrated by receiver operating characteristic 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 MCC patients during therapeutic interventions. CONCLUSIONS: 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 MCC patients.

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