Abstract
Progression occurs in more than 10% of melanoma patients initially diagnosed with local disease, emphasizing the need for improved risk stratification even in early stages. In this study, we used an enrichment method based on recombinant Plasmodium falciparum VAR2CSA protein to enable the capture of rare circulating tumor cells (CTCs) from a single blood draw in early-stage (AJCC I-II) melanoma patients. CTCs were subsequently identified using fluorescent antibodies targeting tumor initiating and melanoma specific cell markers. In parallel, we investigated circulating tumor DNA (ctDNA) in these patients. Among 92 early-stage melanoma patients, CTCs were detected in 21 patients (22.8%) at time of initial diagnosis. The presence of CTCs was significantly associated with an unfavorable clinical outcome, such as disease progression or death related to melanoma disease, with a median observation time of 30 months (IQR 24.0–36.0) (p = 0.043). Furthermore, when combining CTC with ctDNA detection, a highly significant correlation with disease progression was observed (p = 0.014) underlining the role of early tumor cell dissemination in melanoma disease. These findings suggest that CTC assessment, particularly when combined with ctDNA analysis, may represent a valuable biomarker to facilitate risk stratification of early-stage melanoma patients to improve personalized treatment approaches.
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Data availability
The sequence data generated and analyzed during the current study is available in the European Nucleotide Archive (ENA) at EMBL-EBI under accession number PRJEB98726 (https://www.ebi.ac.uk/ena/browser/view/PRJEB98726).
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Acknowledgements
This research was supported, in part, by VAR2 Pharmaceuticals. The funders had no role in data collection and analysis, decision to publish and original draft preparation. We thank the Department of Dermatology (Ordensklinikum Linz Elisabethinen, Austria), the Laboratory for Molecular and Genetic Diagnostics (Ordensklinikum Linz Barmherzige Schwestern, Austria) and the Department of Immunology and Microbiology (University of Copenhagen, Denmark) for the cooperation and providing their clinical, moleculargenetic and biochemical expertise.
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The conducted work was funded by the Department of Dermatology (Ordensklinikum Linz Elisabethinen) and the Laboratory of Molecular Genetic Diagnostics (Ordensklinikum Linz Barmherzige Schwestern) and their research funds.
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J.S and A.S. are co-corresponding authors. J.S. and M.R. designed and conducted the experiments, contributed to data analysis and interpretation and wrote the manuscript; L.L. contributed to data analysis and writing the manuscript; L.S. and V.B. assisted with the analysis; E.S. contributed to patient data collection; K.P., V.P. and H.K. contributed to sample and patient data collection. T.G.T. and P.S. helped with the conceptualization. G.W., A.S., M. Ø.A. and N.S. provided resources and contributed to the conceptualization, validation and editing of the manuscript. J.S., M.R., A.S., M.Ø.A., N.S. did a critical revision of the manuscript for important intellectual content: Final approval of completed version of manuscript: All authors.
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H.K. is consultant for MSD, Bristol Myers Squibb and Pierre Fabre. The aforementioned functions are unrelated to the research presented in this manuscript. The technology to diagnose cancer through rVAR2 is owned by VarCT Diagnostics through a license from VAR2Pharmaceuticals. A.S., T.G.T., M.Ø.A. and P.S. are cofounders of VAR2Pharmaceuticals. The other authors declare no competing interest.
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Sunzenauer, J., Rammer, M., Stöckl, L. et al. Oncofetal chondroitin sulfate positive circulating tumor cells as prognostic biomarkers in early-stage melanoma. Sci Rep (2026). https://doi.org/10.1038/s41598-026-40072-x
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DOI: https://doi.org/10.1038/s41598-026-40072-x
