Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases.

Curtis, SD; Liu, T; Bai, Y; Wang, Y; Panda, S; Li, A; Xu, H; O'Reilly, E; Dobbyn, L; Popoli, M; Ptak, J; Silliman, N; Thoburn, C; Tie, J; Gibbs, P; Ho-Pham, LT; Tran, BNH; Tran, TS; Nguyen, TV; Konig, MF; Petri, M; Rosen, A; Mecoli, CA; Shah, AA; Mulder, F; van Es, N; PLATO-VTE Study Group,; Bettegowda, C; Kinzler, KW; Papadopoulos, N; Vogelstein, JT; Vogelstein, B; Douville, C

Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases.

Curtis, SD Liu, T Bai, Y Wang, Y Panda, S Li, A Xu, H O'Reilly, E Dobbyn, L Popoli, M Ptak, J Silliman, N Thoburn, C Tie, J Gibbs, P Ho-Pham, LT Tran, BNH Tran, TS Nguyen, TV Konig, MF Petri, M Rosen, A Mecoli, CA Shah, AA Mulder, F van Es, N PLATO-VTE Study Group, Bettegowda, C Kinzler, KW Papadopoulos, N Vogelstein, JT Vogelstein, B Douville, C

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Publisher:: Proceedings of the National Academy of Sciences
Publication Type:: Journal Article
Citation:: Proc Natl Acad Sci U S A, 2025, 122, (34), pp. e2426890122
Issue Date:: 2025-08-26

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Field	Value	Language
dc.contributor.author	Curtis, SD
dc.contributor.author	Liu, T
dc.contributor.author	Bai, Y
dc.contributor.author	Wang, Y
dc.contributor.author	Panda, S
dc.contributor.author	Li, A
dc.contributor.author	Xu, H
dc.contributor.author	O'Reilly, E
dc.contributor.author	Dobbyn, L
dc.contributor.author	Popoli, M
dc.contributor.author	Ptak, J
dc.contributor.author	Silliman, N
dc.contributor.author	Thoburn, C
dc.contributor.author	Tie, J
dc.contributor.author	Gibbs, P
dc.contributor.author	Ho-Pham, LT
dc.contributor.author	Tran, BNH
dc.contributor.author	Tran, TS
dc.contributor.author	Nguyen, TV
dc.contributor.author	Konig, MF
dc.contributor.author	Petri, M
dc.contributor.author	Rosen, A
dc.contributor.author	Mecoli, CA
dc.contributor.author	Shah, AA
dc.contributor.author	Mulder, F
dc.contributor.author	van Es, N
dc.contributor.author	PLATO-VTE Study Group,
dc.contributor.author	Bettegowda, C
dc.contributor.author	Kinzler, KW
dc.contributor.author	Papadopoulos, N
dc.contributor.author	Vogelstein, JT
dc.contributor.author	Vogelstein, B
dc.contributor.author	Douville, C
dc.date.accessioned	2026-07-13T05:09:21Z
dc.date.available	2026-07-13T05:09:21Z
dc.date.issued	2025-08-26
dc.identifier.citation	Proc Natl Acad Sci U S A, 2025, 122, (34), pp. e2426890122
dc.identifier.issn	0027-8424
dc.identifier.issn	1091-6490
dc.identifier.uri	http://hdl.handle.net/10453/195635
dc.description.abstract	Multiple case-controlled studies have shown that analyzing fragmentation patterns in plasma cell-free DNA (cfDNA) can distinguish individuals with cancer from healthy controls. However, there have been few studies that investigate various types of cfDNA fragmentomics patterns in individuals with other diseases. We therefore developed a comprehensive statistic, called fragmentation signatures, that integrates the distributions of fragment positioning, fragment length, and fragment end-motifs in cfDNA. We found that individuals with venous thromboembolism, systemic lupus erythematosus, dermatomyositis, or scleroderma have cfDNA fragmentation signatures that closely resemble those found in individuals with advanced cancers. Furthermore, these signatures were highly correlated with increases in inflammatory markers in the blood. We demonstrate that these similarities in fragmentation signatures lead to high rates of false positives in individuals with autoimmune or vascular disease when evaluated using conventional binary classification approaches for multicancer earlier detection (MCED). To address this issue, we introduced a multiclass approach for MCED that integrates fragmentation signatures with protein biomarkers and achieves improved specificity in individuals with autoimmune or vascular disease while maintaining high sensitivity. Though these data put substantial limitations on the specificity of fragmentomics-based tests for cancer diagnostics, they also offer ways to improve the interpretability of such tests. Moreover, we expect these results will lead to a better understanding of the process-most likely inflammatory-from which abnormal fragmentation signatures are derived.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Proceedings of the National Academy of Sciences
dc.relation.ispartof	Proc Natl Acad Sci U S A
dc.relation.isbasedon	10.1073/pnas.2426890122
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Humans
dc.subject.mesh	Neoplasms
dc.subject.mesh	Autoimmune Diseases
dc.subject.mesh	Cell-Free Nucleic Acids
dc.subject.mesh	Vascular Diseases
dc.subject.mesh	Biomarkers
dc.subject.mesh	Case-Control Studies
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Lupus Erythematosus, Systemic
dc.subject.mesh	Humans
dc.subject.mesh	Neoplasms
dc.subject.mesh	Vascular Diseases
dc.subject.mesh	Lupus Erythematosus, Systemic
dc.subject.mesh	Autoimmune Diseases
dc.subject.mesh	Case-Control Studies
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Biomarkers
dc.subject.mesh	Cell-Free Nucleic Acids
dc.subject.mesh	Humans
dc.subject.mesh	Neoplasms
dc.subject.mesh	Autoimmune Diseases
dc.subject.mesh	Cell-Free Nucleic Acids
dc.subject.mesh	Vascular Diseases
dc.subject.mesh	Biomarkers
dc.subject.mesh	Case-Control Studies
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Lupus Erythematosus, Systemic
dc.title	Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases.
dc.type	Journal Article
utslib.citation.volume	122
utslib.location.activity	United States
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Electrical, Mechanical and Biomedical Engineering
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/UTS Ageing Research Collaborative (UARC)
pubs.organisational-group	University of Technology Sydney/UTS Groups/INSIGHT: Institute for Innovative Solutions for Wellbeing and Health
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2026-07-13T05:09:20Z
pubs.issue	34
pubs.publication-status	Published
pubs.volume	122
utslib.citation.issue	34

Abstract:

Multiple case-controlled studies have shown that analyzing fragmentation patterns in plasma cell-free DNA (cfDNA) can distinguish individuals with cancer from healthy controls. However, there have been few studies that investigate various types of cfDNA fragmentomics patterns in individuals with other diseases. We therefore developed a comprehensive statistic, called fragmentation signatures, that integrates the distributions of fragment positioning, fragment length, and fragment end-motifs in cfDNA. We found that individuals with venous thromboembolism, systemic lupus erythematosus, dermatomyositis, or scleroderma have cfDNA fragmentation signatures that closely resemble those found in individuals with advanced cancers. Furthermore, these signatures were highly correlated with increases in inflammatory markers in the blood. We demonstrate that these similarities in fragmentation signatures lead to high rates of false positives in individuals with autoimmune or vascular disease when evaluated using conventional binary classification approaches for multicancer earlier detection (MCED). To address this issue, we introduced a multiclass approach for MCED that integrates fragmentation signatures with protein biomarkers and achieves improved specificity in individuals with autoimmune or vascular disease while maintaining high sensitivity. Though these data put substantial limitations on the specificity of fragmentomics-based tests for cancer diagnostics, they also offer ways to improve the interpretability of such tests. Moreover, we expect these results will lead to a better understanding of the process-most likely inflammatory-from which abnormal fragmentation signatures are derived.

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http://hdl.handle.net/10453/195635