Journal Article

Cross-dataset pan-cancer detection by correlating cell-free DNA fragment coverage with open chromatin sites across cell types

Jakobsen Skanderup, Anders, Jochumsen, Mads Ryø, Henriksen, Tenna Vesterman, Therkildsen, Christina, Kondrup, Karoline, Lamy, Philippe, Demuth, Christina, Rusan, Maria, Buus, Simon, Borre, Michael, Frydendahl, Amanda, Laursen, Britt Elmedal, Andersen, Claus Lindbjerg, Besenbacher, Søren, Holsting, Jakob Qvortrup, Nordentoft, Iver, Bouchelouche, Kirsten, Dyrskjøt, Lars, Rasmussen, Mads Heilskov, Lindskrog, Sia Viborg, Nesic, Marijana, Iisager, Laura, Odinokov, Denis, Olsen, Ludvig Renbo, Sørensen, Karina Dalsgaard

2025

Overview

The fragmentation patterns of whole genome sequenced cell-free DNA are promising features for tumor-agnostic cancer detection. However, systematic biases challenge their cross-cohort generalization. We introduce LIONHEART, an open source cancer detection method specifically optimized to generalize across datasets. The method correlates bias-corrected cfDNA fragment coverage across the genome with the locations of accessible chromatin regions from 898 cell and tissue type features. We use these correlations to detect changes in the cell-free DNA cell type composition caused by cancer. We test LIONHEART on nine datasets and fourteen cancer types (1106 non-cancer controls, 1449 cancers) obtained from different studies and show that it can distinguish cancer samples from non-cancer controls across cohorts with ROC AUC scores ranging from 0.62-0.95 (mean = 0.83, std = 0.12). We further validate the method on an external dataset, achieving a ROC AUC of 0.917. Fragmentation patterns of cell-free DNA are a promising biomarker source, however, correlations with different cancer types are heterogenous. Here, the authors develop LIONHEART to enable detection of 14+ cancer types from whole genome sequenced cell-free DNA.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 631/114/2413 / 631/67/2322 / 692/4017 / Apoptosis / Bias / Binding sites / Biomarkers / Cancer / Cell-Free Nucleic Acids - genetics / Chromatin / Chromatin - genetics / Chromatin - metabolism / Correlation / Datasets / Deoxyribonucleic acid / DNA / DNA fragmentation / Fragmentation / Genomes / Humanities and Social Sciences / Humans / Medical screening / multidisciplinary / Neoplasms - diagnosis / Neoplasms - genetics / Nucleotide sequence / Prostate cancer / ROC Curve / Science / Science (multidisciplinary)