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

• DOI: 10.1038/s41467-024-51529-w
• Publication Date: 2024-08-27T17:03:25Z
• Authors: Derek Wong; Maha Tageldein; Ping Luo; Erik Ensminger; Jeffrey Bruce; Leslie Oldfield; Haifan Gong; Nicholas William ...; Brianne Laverty; Vallijah Subasri; Scott Davidson; Reem Khan; Anita Villani; Adam Shlien; Raymond H. Kim; David Malkin; Trevor J. Pugh
• Keywords: Fragmentation; Li–Fraumeni syndrome

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