Epigenetic Dysregulation of MicroRNA-34A Identified in TP53-Related Cancer Risk
In a genome-wide DNA-methylation analysis to identify genes implicated in Li-Fraumeni syndrome, Samuel et al found a significant association of loss-of-function <em>TP53</em> mutations with differential methylation at the locus encoding microRNA-34A (miR-34A). The study was reported in the Journal of Clinical Oncology.
Study Details
Genome-wide methylation analysis of peripheral blood leukocyte DNA was performed in 72 germline TP53 mutation carriers and 111 patients with wild-type TP53 who had developed histologically comparable malignancies. Targeted bisulfite pyrosequencing was performed in a validation cohort of 30 patients with TP53 mutation and 46 patients with wild-type TP53. Candidate sites were assessed in primary tumors from patients with Li-Fraumeni syndrome who had multiple histologic tumor types.
Methylation Changes
Among all patients in the initial cohort, distinct DNA-methylation signatures were associated with deleterious TP53 mutations. TP53-associated DNA-methylation changes were found in genomic regions with p53-binding sites and in genes encoding p53-pathway proteins. A significant association was observed between loss-of-function TP53 mutations and differential methylation at the locus encoding miR-34A (adjusted P < .001), which plays a primary role in the p53 regulatory network; this finding was confirmed in the validation cohort of 76 patients. Pyrosequencing showed that miR-34A was inactivated by hypermethylation in numerous histologic types of primary tumors from patients with Li-Fraumeni syndrome. In a cohort of 29 patients with choroid plexus carcinoma, a characteristic Li-Fraumeni syndrome tumor, miR-34A hypermethylation was associated with poorer overall survival (P < .05).
The investigators concluded: “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.”
The study was supported by grants from the Canadian Institutes for Health Research, Terry Fox Research Institute, and SickKids Foundation.
David Malkin, MD, of The Hospital for Sick Children, Toronto, Ontario, Canada, is the corresponding author of the Journal of Clinical Oncology article.
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