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Evaluation of circulating Dickkopf-1 as a prognostic biomarker in ovarian cancer patients

Daniel Martin Klotz ORCID logo, Theresa Link, Maren Goeckenjan, Pauline Wimberger, Anna R. Poetsch, Nikolai Jaschke, Lorenz C. Hofbauer, Andy Göbel, Tilman D. Rachner and Jan Dominik Kuhlmann ORCID logo

Abstract

Objectives

Dickkopf-1 (DKK1) is a secreted protein, known for suppressing the differentiation and activity of bone-building osteoblasts by acting as an inhibitor of Wnt-signalling. Soluble DKK1 (sDKK1) has been proposed as prognostic biomarker for a wide range of malignancies, however, clinical relevance of sDKK1 as potential blood-based marker for ovarian cancer is unknown.

Methods

sDKK1 levels were quantified in a cohort of 150 clinically documented ovarian cancer patients by a commercially available DKK1 ELISA (Biomedica, Vienna, Austria).

Results

Median sDKK1 level was significantly elevated at primary diagnosis of ovarian cancer compared to healthy controls (estimated difference (ED) of 7.75 ng/mL (95% CI: 3.01–12.30 ng/mL, p=0.001)). Higher levels of sDKK1 at diagnosis indicated an increased volume of intraoperative malignant ascites (ED 7.08 pmol/L, 95% CI: 1.46–13.05, p=0.02) and predicted suboptimal debulking surgery (ED 6.88 pmol/L, 95% CI: 1.73–11.87, p=0.01). sDKK1 did not correlate with CA125 and higher sDKK1 levels predicted a higher risk of recurrence and poor survival (PFS: HR=0.507, 95% CI: 0.317–0.809; p=0.004; OS: HR=0.561, 95% CI: 0.320–0.986; p=0.044). Prognostic relevance of sDKK1 was partly sustained in wtBRCA patients (PFS: HR=0.507, 95% CI: 0.317–0.809; p=0.004).

Conclusions

This is the first study demonstrating the prognostic relevance of sDKK1 in ovarian cancer patients, including those with wtBRCA 1/2 status. Our data encourage further evaluation of sDKK1 in ovarian cancer patients, possibly in terms of a therapy monitoring marker or a response predictor for sDKK1-directed targeted therapies.


Corresponding author: PD Dr. Jan Dominik Kuhlmann, 1Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; 2German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany; 3National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany, E-mail:
Andy Göbel, Tilman D. Rachner and Jan Dominik Kuhlmann contributed equally to this work.

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: GO 3055/1-1, HO 1875/24-1, 26-1, and 27-1, RA 2151/4-1 and 5-1

Funding source: Deutsche Krebshilfe

Award Identifier / Grant number: 70113573 and as part of the Mildred-Scheel Nachwuchszentrum

Acknowledgments

The authors would like to thank Babett Heschel for her excellent technical assistance.

  1. Research funding: The work was funded by the Deutsche Forschungsgemeinschaft to AG (GO 3055/1-1), LCH (HO 1875/24-1, 26-1, and 27-1) and to TDR (RA 2151/4-1 and 5-1) as part of the DFG Schwerpunktprogramm-2084 µBone as well as by the Deutsche Krebshilfe to AG and TDR (#70113573 and as part of the Mildred-Scheel Nachwuchszentrum).

  2. Author contributions: TDR, AG, DMK, JDK, PW and LCH made substantial contributions to the conception and design of the study. DMK, AG, JDK, TL, MG, NJ contributed to the experimental work or to the acquisition of clinical samples/data or to the analysis/interpretation of the results. JDK, AG and DMK, TL were involved in drafting the manuscript, creating figures or revising the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Written informed consent was obtained from all study participants and the study was approved by the Local Research Ethics Committee in Dresden (EK74032013).

  5. Ethical approval: The study was approved by the Local Research Ethics Committee in Dresden (EK74032013). All study methodologies conformed to the standards set by the Declaration of Helsinki.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2021-0504).


Received: 2021-04-27
Accepted: 2021-10-01
Published Online: 2021-10-25
Published in Print: 2022-01-26

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