This repository is for code to reproduce analyses and figures for the manuscript: Cell-free DNA from germline TP53 mutation carriers reflect cancer-like fragmentation patterns
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 shown shorter cell-free DNA fragmentation, independent of cancer status, in LFS individuals. 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 germline negative LFS patients and provides an important baseline for cancer early detection.
Data required to reproduce the figures can be found at: https://doi.org/10.5281/zenodo.7448381
Author: Derek Wong - derek.wong2@uhnresearch.ca