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

Area of Science:

• Genomics and Molecular Biology
• Cancer Research
• Epigenetics

Background:

• Germline pathogenic TP53 variants define Li-Fraumeni syndrome (LFS), increasing lifetime cancer risk.
• Previous research indicated shorter plasma cell-free DNA (cfDNA) fragmentation in LFS patients, irrespective of cancer status.

Purpose of the Study:

• To investigate the functional basis of cfDNA fragmentation characteristics in LFS.
• To explore the utility of cfDNA fragmentomics for early cancer detection in LFS.

Main Methods:

• Fragmentomic analysis of 199 cfDNA samples from 82 TP53 mutation carriers and 30 healthy controls.
• Assessment of nucleotide prevalence at fragment ends, nucleosome positioning at p53 binding sites, and chromatin accessibility.
• Application of machine learning for classification of TP53 mutant versus wildtype cfDNA.

Main Results:

• LFS individuals displayed increased A/T nucleotides at cfDNA fragment ends.
• Observed dysregulated nucleosome positioning at p53 binding sites and altered chromatin accessibility at specific regulatory regions.
• Machine learning models achieved robust differentiation between TP53 mutant and wildtype cfDNA (AUC-ROC 0.710-1.000).

Conclusions:

• cfDNA fragmentation patterns in LFS are linked to underlying genetic variants and epigenetic alterations.
• cfDNA fragmentomics shows promise as a diagnostic biomarker for LFS.
• Longitudinal ctDNA fragmentation analysis may facilitate early cancer detection in LFS patients.