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

Autor: Wong D; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada., Tageldein M; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Luo P; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada., Ensminger E; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Bruce J; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada., Oldfield L; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada., Gong H; The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada., Fischer NW; The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada., Laverty B; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.; The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada., Subasri V; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.; The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.; Vector Institute, Toronto, Ontario, Canada., Davidson S; Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.; Department of Pediatrics, University of Toronto, Torotno, Ontario, Canada., Khan R; Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.; Department of Pediatrics, University of Toronto, Torotno, Ontario, Canada., Villani A; Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.; Division of Hematology/Oncology, The Hospital for Sick Children, Toroton, Ontario, Canada., Shlien A; Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.; Department of Pediatrics, University of Toronto, Torotno, Ontario, Canada., Kim RH; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Raymond.Kim@uhn.ca.; The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Raymond.Kim@uhn.ca.; Toronto General Hospital Research Institute, Toronto, Ontario, Canada. Raymond.Kim@uhn.ca.; Ontario Institute of Cancer Research, Toronto, Ontario, Canada. Raymond.Kim@uhn.ca., Malkin D; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. david.malkin@sickkids.ca.; Department of Pediatrics, University of Toronto, Torotno, Ontario, Canada. david.malkin@sickkids.ca.; Toronto General Hospital Research Institute, Toronto, Ontario, Canada. david.malkin@sickkids.ca., Pugh TJ; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. trevor.pugh@utoronto.ca.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. trevor.pugh@utoronto.ca.; Ontario Institute of Cancer Research, Toronto, Ontario, Canada. trevor.pugh@utoronto.ca.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 27; Vol. 15 (1), pp. 7386. Date of Electronic Publication: 2024 Aug 27.
DOI: 10.1038/s41467-024-51529-w
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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