Pan-cancer Graph-based Cancer Detection Using the Cell-free DNA Methylome

Motivation: Cell-free DNA methylation provides a minimally invasive signal for early cancer detection and tissue-of-origin prediction. Most methods represent methylation measurements as independent fixed-window features and therefore do not explicitly model relationships among genomic regions. Results: We developed PANGEM (Pan-cancer Graph-based Cancer Detection Using the Cell-free DNA Methylome), a graph-learning framework that represents genomic bins as nodes and integrates CpG context, genomic proximity, and sample-specific methylation similarity in the graph topology. Across five repeated stratified train-test splits, PANGEM achieved the highest mean performance among evaluated methods, with an AUROC/AUPR of 0.997/1.000 for binary cancer detection and macro-AUROC/AUPR of 0.977/0.870 for multiclass tissue-of-origin prediction. In the independent INSPIRE cohort, 72 of 78 cancer cases (92.3%) exceeded the binary classification threshold, and PANGEM correctly classified 9 of 17 head and neck cancer cases (52.9%), the highest accuracy among evaluated methods. Subnetwork analysis further identified recurrent, graph-connected methylation patterns, including a 111-DMR subnetwork with increased methylation in cancer samples.