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Clin Cancer Res. 2018 Dec 1;24(23):5873-5882. doi: 10.1158/1078-0432.CCR-18-1184. Epub 2018 Jul 30.

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

Author information

1
Department of Dermatology, Medical University of Graz, Graz, Austria.
2
Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany.
3
German Cancer Consortium (DKTK), Essen, Germany.
4
German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Department of Dermatology/Medicine, University of Washington, Seattle, Washington.
6
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
7
Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
8
Centre for Cancer Research, University of Melbourne, Melbourne, Australia.
9
Peter MacCallum Cancer Centre, Melbourne, Australia.
10
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
11
Department of Dermatology, Ruhr-University Bochum, Bochum, Germany.
12
Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
13
Department of Dermatology, University Hospital Essen, Essen, Germany.
14
Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany. j.becker@dkfz.de.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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 (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) 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.

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 patients with MCC.

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