Peripheral blood DNA methylation predicts the early onset of primary tumor in TP53 mutation carriers

作者：Vallijah Subasri, Benjamin Brew, Brianne Laverty, Lauren Erdman, Tanya Guha, Jordan R. Hansford, Elizabeth Cairney, Carol Portwine, Christine Elser, Jonathan L. Finlay, Kim E. Nichols, Jo Anson, Wendy Kohlmann, Haifan Gong, Jodi Lees, Noa Alon, Ledia Brunga, Anita Villani, Kelvin C. de Andrade, Payal P. Khincha, Sharon A. Savage, Joshua D. Schiffman, Trevor J. Pugh, David Malkin, Anna Goldenberg · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-62894-5 · 被引用次数：2 · 研究领域：Epigenetics and DNA Methylation、Cancer-related Molecular Pathways、Cancer Genomics and Diagnostics

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. Li-Fraumeni syndrome leads to an increased predisposition to tumour development. Here, the authors develop a support vector machine model to predict early cancer risk in individuals using peripheral blood DNA methylation profiles.