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Samuel N, Wilson G, Lemire M, et al. Genome-Wide DNA Methylation Analysis Reveals Epigenetic Dysregulation of MicroRNA-34A in TP53-Associated Cancer Susceptibility. J Clin Oncol. 2016;34(30):3697-3704doi: 10.1200/JCO.2016.67.6940.
Samuel, N., Wilson, G., Lemire, M., Id Said, B., Lou, Y., Li, W., Merino, D., Novokmet, A., Tran, J., Nichols, K. E., Finlay, J. L., Choufani, S., Remke, M., Ramaswamy, V., Cavalli, F. M. G., Elser, C., Meister, L., Taylor, M. D., Tabori, U., Irwin, M., Weksberg, R., Wasserman, J. D., Paterson, A. D., Hansford, J. R., Achatz, M. I. W., Hudson, T. J., & Malkin, D. (2016). Genome-Wide DNA Methylation Analysis Reveals Epigenetic Dysregulation of MicroRNA-34A in TP53-Associated Cancer Susceptibility. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 34(30), 3697-3704. https://doi.org/10.1200/JCO.2016.67.6940
Samuel, Nardin, et al. "Genome-Wide DNA Methylation Analysis Reveals Epigenetic Dysregulation of MicroRNA-34A in TP53-Associated Cancer Susceptibility." Journal of clinical oncology : official journal of the American Society of Clinical Oncology vol. 34,30 (2016): 3697-3704. doi: https://doi.org/10.1200/JCO.2016.67.6940
Samuel N, Wilson G, Lemire M, Id Said B, Lou Y, Li W, Merino D, Novokmet A, Tran J, Nichols KE, Finlay JL, Choufani S, Remke M, Ramaswamy V, Cavalli FMG, Elser C, Meister L, Taylor MD, Tabori U, Irwin M, Weksberg R, Wasserman JD, Paterson AD, Hansford JR, Achatz MIW, Hudson TJ, Malkin D. Genome-Wide DNA Methylation Analysis Reveals Epigenetic Dysregulation of MicroRNA-34A in TP53-Associated Cancer Susceptibility. J Clin Oncol. 2016 Oct 20;34(30):3697-3704. doi: 10.1200/JCO.2016.67.6940. PMID: 27551116; PMCID: PMC6366343.
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J Clin Oncol. 2016 Oct 20;34(30):3697-3704. doi: 10.1200/JCO.2016.67.6940.

Genome-Wide DNA Methylation Analysis Reveals Epigenetic Dysregulation of MicroRNA-34A in TP53-Associated Cancer Susceptibility.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Nardin Samuel, Gavin Wilson, Mathieu Lemire, Badr Id Said, Youliang Lou, Weili Li, Diana Merino, Ana Novokmet, James Tran, Kim E Nichols, Jonathan L Finlay, Sanaa Choufani, Marc Remke, Vijay Ramaswamy, Florence M G Cavalli, Christine Elser, Lynn Meister, Michael D Taylor, Uri Tabori, Meredith Irwin, Rosanna Weksberg, Jonathan D Wasserman, Andrew D Paterson, Jordan R Hansford, Maria Isabel W Achatz, Thomas J Hudson, David Malkin

Affiliations

  1. Nardin 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.

PMID: 27551116 PMCID: PMC6366343 DOI: 10.1200/JCO.2016.67.6940

Abstract

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.

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