Peripheral blood DNA methylation predicts the early onset of primary tumor in TP53 mutation carriers
Li-Fraumeni syndrome (LFS) confers high lifetime cancer risk due to germline TP53 pathogenic variants (PV). A comprehensive surveillance regimen termed the 'Toronto Protocol', has been adopted for early tumor detection, demonstrating improved survival among TP53 PV carriers. However, the protocol's "one-size-fits-all" approach fails to consider individual cancer risk. To personalize screening, we developed a support vector machine model to predict early onset of primary tumors (age < 6) using peripheral blood methylation data of TP53 PV carriers (n = 237). Validation (n = 64) and external testing (n = 79) showed AUROC = 0.928 [0.835-1.000], F1-score = 0.692 [0.435-0.867], and NPV = 0.984 [0.946-1.000]. The model achieved 91% accuracy, correctly classifying 90% of patients with cancer before the age of six and 87% of cancer-free individuals in the external test set. Our tool enables risk stratification for early-onset malignancies, to optimize clinical surveillance and improve patient outcomes.
Authors
- Anita Villani (ORCID: https://orcid.org/0000-0003-3283-2197)
- Sharon A. Savage (ORCID: https://orcid.org/0000-0001-6006-0740)
- Ledia Brunga (ORCID: https://orcid.org/0000-0003-0343-937X)
- Vallijah Subasri (ORCID: https://orcid.org/0000-0002-6584-877X)
- Kim E. Nichols (ORCID: https://orcid.org/0000-0002-5581-6555)
- Jordan R. Hansford (ORCID: https://orcid.org/0000-0001-7733-383X)
- Joshua David Schiffman (ORCID: https://orcid.org/0000-0002-6968-7694)
- Haifan Gong (ORCID: https://orcid.org/0009-0001-2645-6837)
- Jodi Lees
- Brianne Laverty (ORCID: https://orcid.org/0000-0002-7245-0831)
- Payal P. Khincha (ORCID: https://orcid.org/0000-0003-2473-7800)
- Elizabeth Cairney (ORCID: https://orcid.org/0000-0003-1569-8838)
- Kelvin C. de Andrade (ORCID: https://orcid.org/0000-0003-4651-996X)
- Tanya Guha
- Jo Anson
- Christine Elser (ORCID: https://orcid.org/0000-0003-0003-713X)
- Carol Portwine (ORCID: https://orcid.org/0000-0002-1314-8691)
- Trevor J. Pugh (ORCID: https://orcid.org/0000-0002-8073-5888)
- Jonathan L. Finlay (ORCID: https://orcid.org/0000-0002-8312-6586)
- Benjamin Brew
- Wendy Kohlmann
- Noa Alon (ORCID: https://orcid.org/0000-0001-9483-1785)
- Anna Goldenberg (ORCID: https://orcid.org/0000-0002-2416-833X)
- David M. Malkin (ORCID: https://orcid.org/0000-0001-5752-9763)
- Lauren Erdman (ORCID: https://orcid.org/0000-0002-7106-2669)
Institutions
- Canadian Institute for Advanced Research (CA)
- Ontario Institute for Cancer Research (CA)
- Western University (CA)
- Mount Sinai Hospital (CA)
- National Institutes of Health (US)
- St. Jude Children's Research Hospital (US)
- Royal Children's Hospital (AU)
- University Health Network (CA)
- The University of Melbourne (AU)
- University of Toronto (CA)
- University of Utah (US)
- London Health Sciences Centre (CA)
- Huntsman Cancer Institute (US)
- Women's and Children's Hospital (AU)
- Hospital for Sick Children (CA)
- Princess Margaret Cancer Centre (CA)
- Vector Institute (CA)
- South Australian Health and Medical Research Institute (AU)
- Centre for Cancer Biology (AU)
- National Cancer Institute (US)
- SickKids Foundation (CA)
- Murdoch Children's Research Institute (AU)
- The Ohio State University (US)
- The University of Adelaide (AU)
- McMaster University (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-26
- DOI
- https://doi.org/10.1038/s41467-025-62894-5
- Citations
- 1
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Ohio State University
- Canadian Institute for Advanced Research
- London Health Sciences Centre
- McMaster University
- Huntsman Cancer Institute
- Children’s Hospital of Wisconsin Research Institute
- Murdoch Children's Research Institute
- Canada Research Chairs
- University of Toronto
- Terry Fox Research Institute
- Hospital for Sick Children
- Robert Connor Dawes Foundation
- National Institutes of Health
- Garron Family Cancer Centre
- National Cancer Institute
- CIHR Skin Research Training Centre
- Division of Cancer Epidemiology and Genetics, National Cancer Institute