Cell-free DNA from germline TP53 mutation carriers reflect cancer-like fragmentation patterns

Derek Wong, Maha Tageldein, Ping Luo, Erik Ensminger, Jeffrey Bruce, Leslie Oldfield, Haifan Gong, Nicholas William Fischer, Brianne Laverty, Vallijah Subasri, Scott Davidson, Reem Khan, Anita Villani, Adam Shlien, Raymond H. Kim (), David Malkin () and Trevor J. Pugh ()
Additional contact information
Derek Wong: University Health Network
Maha Tageldein: University Health Network
Ping Luo: University Health Network
Erik Ensminger: University Health Network
Jeffrey Bruce: University Health Network
Leslie Oldfield: University Health Network
Haifan Gong: University of Toronto
Nicholas William Fischer: University of Toronto
Brianne Laverty: University of Toronto
Vallijah Subasri: University of Toronto
Scott Davidson: The Hospital for Sick Children Research Institute
Reem Khan: The Hospital for Sick Children Research Institute
Anita Villani: The Hospital for Sick Children Research Institute
Adam Shlien: The Hospital for Sick Children Research Institute
Raymond H. Kim: University Health Network
David Malkin: University of Toronto
Trevor J. Pugh: University Health Network

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Germline pathogenic TP53 variants predispose individuals to a high lifetime risk of developing multiple cancers and are the hallmark feature of Li-Fraumeni syndrome (LFS). Our group has previously shown that LFS patients harbor shorter plasma cell-free DNA fragmentation; independent of cancer status. To understand the functional underpinning of cfDNA fragmentation in LFS, we conducted a fragmentomic analysis of 199 cfDNA samples from 82 TP53 mutation carriers and 30 healthy TP53-wildtype controls. We find that LFS individuals exhibit an increased prevalence of A/T nucleotides at fragment ends, dysregulated nucleosome positioning at p53 binding sites, and loci-specific changes in chromatin accessibility at development-associated transcription factor binding sites and at cancer-associated open chromatin regions. Machine learning classification resulted in robust differentiation between TP53 mutant versus wildtype cfDNA samples (AUC-ROC = 0.710–1.000) and intra-patient longitudinal analysis of ctDNA fragmentation signal enabled early cancer detection. These results suggest that cfDNA fragmentation may be a useful diagnostic tool in LFS patients and provides an important baseline for cancer early detection.

Date: 2024
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DOI: 10.1038/s41467-024-51529-w

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