Cell-free DNA fragmentomes for noninvasive detection of liver cirrhosis and other diseases
Accessible liquid biopsies, including analyses of genome-wide cell-free DNA (cfDNA) fragmentation, are emerging for early detection of cancer but remain largely unexplored in other diseases. Here, we used whole-genome sequencing to examine cfDNA fragmentomes in 1576 individuals, including those with liver disease or with other morbidities such as vascular, autoimmune, and neurodegenerative conditions. As a prototype for disease-specific cfDNA fragmentomic biomarkers, we developed a machine learning classifier that detected early liver disease, advanced fibrosis, and cirrhosis with high sensitivity in separate discovery (<i>n</i> = 423) and validation cohorts (<i>n</i> = 221) and had limited cross-reactivity for other diseases. Genome-wide fragmentome and methylome analyses revealed liver-derived and immune-mediated changes in cfDNA in the circulation of individuals affected with liver disease. Fragmentomic changes were also observed across a range of other human morbidities and reflected disease-specific changes in the circulation. A machine learning model using cfDNA fragmentomes predicted overall survival in separate morbidity discovery (<i>n</i> = 571) and validation cohorts (<i>n</i> = 231). These analyses demonstrate the connection between cfDNA fragmentomes and an individual's physiologic state and provide previously unrecognized possibilities for cfDNA liquid biopsies across human disease.
Authors
- Michaël Noë (ORCID: https://orcid.org/0000-0002-5336-4508)
- Adrianna L. Bartolomucci
- Shashikant Koul (ORCID: https://orcid.org/0000-0002-9690-7349)
- Nicholas A. Vulpescu (ORCID: https://orcid.org/0000-0003-1310-0257)
- Zachariah H. Foda (ORCID: https://orcid.org/0000-0002-3591-8482)
- Simona Dima (ORCID: https://orcid.org/0000-0001-5275-8938)
- Jamie E. Medina (ORCID: https://orcid.org/0000-0002-6124-0548)
- Sarah Bacus
- Răzvan Iacob (ORCID: https://orcid.org/0000-0002-8545-310X)
- Akshaya V. Annapragada (ORCID: https://orcid.org/0000-0002-9097-6511)
- Dimitrios Mathios (ORCID: https://orcid.org/0000-0002-0792-6880)
- Amy K. Kim (ORCID: https://orcid.org/0000-0001-6121-9581)
- Nicholas C. Dracopoli (ORCID: https://orcid.org/0000-0003-3962-4059)
- Carter Norton (ORCID: https://orcid.org/0009-0001-4991-6998)
- Bryan Chesnick
- Jacob Carey (ORCID: https://orcid.org/0000-0001-9462-206X)
- Vilmos Adleff (ORCID: https://orcid.org/0000-0002-5001-1766)
- Jillian Phallen (ORCID: https://orcid.org/0000-0002-5492-9013)
- John D. Groopman (ORCID: https://orcid.org/0000-0003-4690-2133)
- Keerti Boyapati (ORCID: https://orcid.org/0009-0009-3769-5452)
- Noushin Niknafs (ORCID: https://orcid.org/0000-0002-4852-3674)
- Claus Larsen Feltoft
- Hope Orjuela
- Sarah Short (ORCID: https://orcid.org/0000-0003-2319-6360)
- Liana Gheorghe
- Chris Cherry
- J. D. Johansen
- Victor E. Velculescu
- Gregory D. Kirk
- Daniel C. Bruhm
- Alessandro Leal
- Katherine A. McGlynn
- Speranta Iacob
- Stephen B. Baylin
- Andrei Sorop
- Robert B. Scharpf
Institutions
- Johns Hopkins University (US)
- Carol Davila University of Medicine and Pharmacy (RO)
- Washington University in St. Louis (US)
- Johns Hopkins Medicine (US)
- Herlev Hospital (DK)
- Gentofte Hospital (DK)
- CCC Diagnostics (United States) (US)
- Sequella (United States) (US)
- National Institute of Research and Development for Biological Sciences (RO)
- Hope Center for Neurological Disorders (US)
- Institute of Nutrition of Central America and Panama (GT)
- National Cancer Institute (US)
- Institutul Clinic Fundeni (RO)
- Sidney Kimmel Comprehensive Cancer Center (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2026-03-04
- DOI
- https://doi.org/10.1126/scitranslmed.adw2603
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 0.00