DNA Methylation Profiling in Melanoma: From Lesion Classification to Therapeutic Stratification
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: DNA methylation provides a stable record of cellular identity, capturing epigenetic programs that distinguish specialized cell states despite a shared genome. Because malignant transformation and tumour progression are accompanied by extensive epigenetic remodeling, we hypothesized that the methylome of melanocytic lesions contains biologically and clinically relevant information for both diagnosis and disease progression. In a cohort of 1,001 tissue samples prospectively collected across eight German university hospitals profiled using Illumina Infinium MethylationEPIC arrays, we compared machine-learning models based on selected Cytosine phosphate Guanine (CpG) methylation sites with models incorporating biology-guided features, including epigenetic age acceleration, cell type composition and copy-number variation burden. In an external test set, the best diagnostic classifier was CpG-based and distinguished melanocytic nevi, noninvasive melanoma and invasive melanoma with a macro-averaged area under the receiver operating characteristic curve of 0.919 (95% CI: 0.878 to 0.952). Notably, across CpGs most strongly hyper- and hypomethylated between NV and IM, NIM showed an intermediate methylation profile, providing a molecular correlate of its diagnostic complexity. The best model for clinically relevant treatment group prediction, with AJCC stages grouped according to guideline-based management recommendations, relied on biology-guided features and achieved a macro-averaged mean absolute error of 0.627 (95% CI: 0.477 to 0.808). Together, these findings demonstrate that methylation-based models can capture both diagnostic identity and clinically relevant disease stratification, supporting DNA methylation as a promising biomarker for further validation and potential clinical translation.
Source: arXiv (Cornell University)
Authors: Winterstein, Jana T., Heinlein, Lukas, Raddatz, Günter, Garcia, Carina Nogueira, Haggenmüller, Sarah, Wies, Christoph, Schneider, Lucas, Hoffsommer, Annemarie, Zeuner, Tim J., Meier, Friedegund, Hobelsberger, Sarah, Gellrich, Frank F., Sergon, Mildred, Hauschild, Axel, Heinzerling, Lucie, Schlager, Justin G., Ghoreschi, Kamran, Schlaak, Max, Hilke, Franz J., Berking, Carola, Heppt, Markus V., Erdmann, Michael, Haferkamp, Sebastian, Drexler, Konstantin, Schadendorf, Dirk, Sondermann, Wiebke, Goebeler, Matthias, Schilling, Bastian, Lipka, Daniel B., Fröhling, Stefan, Sahm, Felix, Kather, Jakob N., Tolkach, Yuri, Utikal, Jochen S., Izar, Benjamin, Semenov, Yevgeniy R., Brinker, Titus J.
Institutions: German Cancer Research Center, University Hospital Heidelberg, University Hospital Carl Gustav Carus, University Hospital Schleswig-Holstein, Friedrich-Alexander-Universität Erlangen-Nürnberg, LMU Klinikum, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen, Ludwig-Maximilians-Universität München, Charité – Universitätsmedizin Berlin, University Hospital Regensburg, Essen University Hospital, Universitätsklinikum Würzburg, Goethe University Frankfurt, University Hospital Frankfurt, University of Cologne, University Hospital Cologne
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: Deutsches Krebsforschungszentrum
OpenAlex ID: W7204167521