Cell-free DNA from germline TP53 mutation carriers reflect cancer-like fragmentation patterns.
Humans
Tumor Suppressor Protein p53
/ genetics
Germ-Line Mutation
Male
Female
Li-Fraumeni Syndrome
/ genetics
Cell-Free Nucleic Acids
/ genetics
Adult
DNA Fragmentation
Young Adult
Middle Aged
Circulating Tumor DNA
/ genetics
Adolescent
Neoplasms
/ genetics
Chromatin
/ genetics
Machine Learning
Heterozygote
Child
Nucleosomes
/ metabolism
Early Detection of Cancer
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 Aug 2024
27 Aug 2024
Historique:
received:
11
09
2023
accepted:
07
08
2024
medline:
28
8
2024
pubmed:
28
8
2024
entrez:
27
8
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39191772
doi: 10.1038/s41467-024-51529-w
pii: 10.1038/s41467-024-51529-w
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
TP53 protein, human
0
Cell-Free Nucleic Acids
0
Circulating Tumor DNA
0
Chromatin
0
Nucleosomes
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7386Informations de copyright
© 2024. The Author(s).
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