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

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

doi:10.1038/s41467-025-62894-5

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

Nat Commun. 2025 Aug 26;16(1):7976. doi: 10.1038/s41467-025-62894-5.

Authors

Vallijah Subasri^#^{1

2

3}, Benjamin Brew^#¹, Brianne Laverty^{1

2}, Lauren Erdman^{1

3

4}, Tanya Guha^{1

5}, Jordan R Hansford^{6

7

8

9

10

11}, Elizabeth Cairney^{12

13}, Carol Portwine¹⁴, Christine Elser^{15

16

17}, Jonathan L Finlay¹⁸, Kim E Nichols¹⁹, Jo Anson²⁰, Wendy Kohlmann²⁰, Haifan Gong¹, Jodi Lees¹, Noa Alon¹, Ledia Brunga¹, Anita Villani^{21

22}, Kelvin C de Andrade²³, Payal P Khincha²³, Sharon A Savage²³, Joshua D Schiffman²⁴, Trevor J Pugh^{2

25

26}, David Malkin^{27

28

29

30

31}, Anna Goldenberg^{32

33

34

35}

Affiliations

¹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
² Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
³ Vector Institute, Toronto, ON, Canada.
⁴ Department of Computer Science, University of Toronto, Toronto, ON, Canada.
⁵ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
⁶ Children's Cancer Centre, Royal Children's Hospital, Melbourne, VIC, Australia.
⁷ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁸ Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia.
⁹ Michael Rice Centre for Haematology and Oncology, Women's and Children's Hospital, Adelaide, SA, Australia.
¹⁰ South Australia Health and Medical Research Institute, Adelaide, SA, Australia.
¹¹ South Australia Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia.
¹² Department of Pediatrics, Children's Hospital at London Health Sciences Centre, London, ON, Canada.
¹³ Department of Pediatrics, Western University, London, ON, Canada.
¹⁴ Department of Pediatrics, McMaster University, Hamilton, ON, Canada.
¹⁵ Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁶ Department of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada.
¹⁷ Department of Medical Oncology, Mount Sinai Hospital, Toronto, ON, Canada.
¹⁸ Pediatrics and Radiation Oncology, The Ohio State University College of Medicine, Columbus, OH, USA.
¹⁹ Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
²⁰ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
²¹ Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
²² Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
²³ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
²⁴ Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
²⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
²⁶ Ontario Institute for Cancer Research, Toronto, OH, Canada.
²⁷ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada. david.malkin@sickkids.ca.
²⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. david.malkin@sickkids.ca.
²⁹ Institute of Medical Science, University of Toronto, Toronto, ON, Canada. david.malkin@sickkids.ca.
³⁰ Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada. david.malkin@sickkids.ca.
³¹ Department of Pediatrics, University of Toronto, Toronto, ON, Canada. david.malkin@sickkids.ca.
³² Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada. anna.goldenberg@sickkids.ca.
³³ Vector Institute, Toronto, ON, Canada. anna.goldenberg@sickkids.ca.
³⁴ Department of Computer Science, University of Toronto, Toronto, ON, Canada. anna.goldenberg@sickkids.ca.
³⁵ CIFAR, Toronto, ON, Canada. anna.goldenberg@sickkids.ca.

^# Contributed equally.

Abstract

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.

MeSH terms

Adolescent
Adult
Age of Onset
Child
Child, Preschool
DNA Methylation* / genetics
Early Detection of Cancer / methods
Female
Germ-Line Mutation
Heterozygote
Humans
Li-Fraumeni Syndrome* / blood
Li-Fraumeni Syndrome* / diagnosis
Li-Fraumeni Syndrome* / genetics
Male
Middle Aged
Mutation
Neoplasms* / blood
Neoplasms* / diagnosis
Neoplasms* / genetics
Support Vector Machine
Tumor Suppressor Protein p53* / genetics
Young Adult

Substances

Tumor Suppressor Protein p53
TP53 protein, human

Abstract

MeSH terms

Substances

Grants and funding