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

Kaiji Fan; Cathrin Ritter; Paul Nghiem; Astrid Blom; Monique E. Verhaegen; Andrzej Dlugosz; Niels Dum; Anders Woetmann; Richard W. Tothill; Rodney J. Hicks; Michael Sand; David Schrama; Dirk Schadendorf; Selma Ugurel; Jurgen C. Becker

doi:10.1158/1078-0432.ccr-18-1184

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

Kaiji Fan, Cathrin Ritter, Paul Nghiem, Astrid Blom, Monique E. Verhaegen, Andrzej Dlugosz, Niels Dum, Anders Woetmann, Richard W. Tothill, Rodney J. Hicks, Michael Sand, David Schrama, Dirk Schadendorf, Selma Ugurel, Jurgen C. Becker^*

^*Corresponding author for this work

27 Citations (Scopus)

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 ¼ 0.037) but not in tumor-free (P ¼ 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 ¼ 0.954 and 0.800) as well as in the prospective cohorts (AUC ¼ 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.

Original language	English
Journal	Clinical Cancer Research
Volume	24
Issue number	23
Pages (from-to)	5873-5882
Number of pages	10
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.ccr-18-1184
Publication status	Published - 2018

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Fan, K., Ritter, C., Nghiem, P., Blom, A., Verhaegen, M. E., Dlugosz, A., Dum, N., Woetmann, A., Tothill, R. W., Hicks, R. J., Sand, M., Schrama, D., Schadendorf, D., Ugurel, S., & Becker, J. C. (2018). Circulating cell-free miR-375 as surrogate marker of tumor burden in Merkel cell carcinoma. Clinical Cancer Research, 24(23), 5873-5882. https://doi.org/10.1158/1078-0432.ccr-18-1184

Fan, K, Ritter, C, Nghiem, P, Blom, A, Verhaegen, ME, Dlugosz, A, Dum, N , Woetmann, A, Tothill, RW, Hicks, RJ, Sand, M, Schrama, D, Schadendorf, D, Ugurel, S & Becker, JC 2018, 'Circulating cell-free miR-375 as surrogate marker of tumor burden in Merkel cell carcinoma', Clinical Cancer Research, vol. 24, no. 23, pp. 5873-5882. https://doi.org/10.1158/1078-0432.ccr-18-1184

@article{e2fba8069a5942299a170b04e40dc444,

title = "Circulating cell-free miR-375 as surrogate marker of tumor burden in Merkel cell carcinoma",

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 ¼ 0.037) but not in tumor-free (P ¼ 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 ¼ 0.954 and 0.800) as well as in the prospective cohorts (AUC ¼ 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.",

author = "Kaiji Fan and Cathrin Ritter and Paul Nghiem and Astrid Blom and Verhaegen, {Monique E.} and Andrzej Dlugosz and Niels Dum and Anders Woetmann and Tothill, {Richard W.} and Hicks, {Rodney J.} and Michael Sand and David Schrama and Dirk Schadendorf and Selma Ugurel and Becker, {Jurgen C.}",

year = "2018",

doi = "10.1158/1078-0432.ccr-18-1184",

language = "English",

volume = "24",

pages = "5873--5882",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research (A A C R)",

number = "23",

}

TY - JOUR

T1 - Circulating cell-free miR-375 as surrogate marker of tumor burden in Merkel cell carcinoma

AU - Fan, Kaiji

AU - Ritter, Cathrin

AU - Nghiem, Paul

AU - Blom, Astrid

AU - Verhaegen, Monique E.

AU - Dlugosz, Andrzej

AU - Dum, Niels

AU - Woetmann, Anders

AU - Tothill, Richard W.

AU - Hicks, Rodney J.

AU - Sand, Michael

AU - Schrama, David

AU - Schadendorf, Dirk

AU - Ugurel, Selma

AU - Becker, Jurgen C.

PY - 2018

Y1 - 2018

N2 - 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 ¼ 0.037) but not in tumor-free (P ¼ 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 ¼ 0.954 and 0.800) as well as in the prospective cohorts (AUC ¼ 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.

AB - 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 ¼ 0.037) but not in tumor-free (P ¼ 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 ¼ 0.954 and 0.800) as well as in the prospective cohorts (AUC ¼ 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.

U2 - 10.1158/1078-0432.ccr-18-1184

DO - 10.1158/1078-0432.ccr-18-1184

M3 - Journal article

C2 - 30061360

AN - SCOPUS:85057197183

SN - 1078-0432

VL - 24

SP - 5873

EP - 5882

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 23

ER -

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

Abstract

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