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Updated: Mar 16, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Genome-Wide DNA Methylation Analysis Reveals Epigenetic Dysregulation of MicroRNA-34A in TP53-Associated Cancer
Nardin Samuel1, Gavin Wilson1, Mathieu Lemire1
1Nardin Samuel, Gavin Wilson, James Tran, Meredith Irwin, Rosanna Weksberg, Thomas J. Hudson, and David Malkin, University of Toronto; Nardin Samuel, Badr Id Said, Youliang Lou, Weili Li, Ana Novokmet, James Tran, Sanaa Choufani, Marc Remke, Vijay Ramaswamy, Florence M.G. Cavalli, Michael D. Taylor, Uri Tabori, Meredith Irwin, Rosanna Weksberg, Jonathan D. Wasserman, Andrew D. Paterson, and David Malkin, The Hospital for Sick Children; Nardin Samuel, Gavin Wilson, Mathieu Lemire, and Thomas J. Hudson, Ontario Institute for Cancer Research; Christine Elser, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Diana Merino, National Institutes of Health, Bethesda, MD; Kim E. Nichols, St Jude Children's Research Hospital, Memphis, TN; Jonathan L. Finlay, Nationwide Children's Hospital, Columbus, OH; Lynn Meister, Joe DiMaggio Children's Hospital, Hollywood, FL; Jordan R. Hansford, Children's Cancer Centre, Royal Children's Hospital, Melbourne, Victoria, Australia; and Maria Isabel W. Achatz, Hospital AC Camargo, São Paulo, Brazil.
Purpose:
Although the link between mutant TP53 and human cancer is unequivocal, a significant knowledge gap exists in clinically actionable molecular targets in Li-Fraumeni syndrome (LFS), a highly penetrant cancer predisposition syndrome associated with germline mutations in TP53. This study surveyed the epigenome to identify functionally and clinically relevant novel genes implicated in LFS.
Patients And Methods:
We performed genome-wide methylation analyses of peripheral blood leukocyte DNA in germline TP53 mutation carriers (n = 72) and individuals with TP53 wild type in whom histologically comparable malignancies developed (n = 111). Targeted bisulfite pyrosequencing was performed on a validation cohort of 30 TP53 mutation carriers and 46 patients with TP53 wild type, and candidate sites were evaluated in primary tumors from patients with LFS across multiple histologic tumor types.
Results:
In 183 patients, distinct DNA methylation signatures were associated with deleterious TP53 mutations in peripheral blood leukocytes. TP53-associated DNA methylation marks occurred in genomic regions that harbored p53 binding sites and in genes encoding p53 pathway proteins. Moreover, loss-of-function TP53 mutations were significantly associated with differential methylation at the locus encoding microRNA miR-34A, a key component of the p53 regulatory network (adjusted P < .001), and validated in an independent patient cohort (n = 76, P < .001). Targeted bisulfite pyrosequencing demonstrated that miR-34A was inactivated by hypermethylation across many histologic types of primary tumors from patients with LFS. Moreover, miR-34A tumor hypermethylation was associated with decreased overall survival in a cohort of 29 patients with choroid plexus carcinomas, a characteristic LFS tumor (P < .05).
Conclusion:
Epigenetic dysregulation of miR-34A may comprise an important path in TP53-associated cancer predisposition and represents a therapeutically actionable target with potential clinical relevance.
Insights
Li-Fraumeni syndrome (LFS) involves TP53 mutations and cancer. Epigenetic analysis revealed miR-34A hypermethylation in LFS tumors, suggesting it as a therapeutic target for TP53-associated cancers.
Area of Science:
- Genomics and epigenomics
- Cancer predisposition syndromes
- Molecular oncology
Background:
- Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome.
- Germline mutations in TP53 are unequivocally linked to cancer.
- Clinically actionable molecular targets for LFS remain largely unknown.
Purpose of the Study:
- To survey the epigenome in LFS.
- To identify novel, functionally and clinically relevant genes implicated in LFS.
- To investigate potential therapeutic targets in TP53-associated cancers.
Main Methods:
- Genome-wide methylation analysis of peripheral blood leukocyte DNA.
- Analysis of TP53 mutation carriers (n=72) and wild-type controls (n=111).
- Targeted bisulfite pyrosequencing and evaluation in primary LFS tumors.
Main Results:
- Distinct DNA methylation signatures associated with deleterious TP53 mutations were identified.
- TP53 mutations correlated with methylation changes in p53 binding sites and p53 pathway genes.
- Loss-of-function TP53 mutations significantly associated with differential methylation of microRNA miR-34A (P < .001).
- miR-34A inactivation by hypermethylation observed in LFS tumors.
- miR-34A tumor hypermethylation linked to decreased survival in choroid plexus carcinomas (P < .05).
Conclusions:
- Epigenetic dysregulation of miR-34A is implicated in TP53-associated cancer predisposition.
- miR-34A represents a therapeutically actionable target for LFS.
- This finding has potential clinical relevance for managing LFS.
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