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I4C Epigenetics Working Group

I4C Epigenetics Working Group. Barcelona, September 2011. Proposal. Exploratory section: An epigenetic signature of childhood cancer obtained at birth Screening section: An epigenetic signature of cancer predisposition linked to high birth weight. Objectives.

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I4C Epigenetics Working Group

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  1. I4C Epigenetics Working Group Barcelona, September 2011

  2. Proposal • Exploratory section: An epigenetic signature of childhood cancer obtained at birth • Screening section: An epigenetic signature of cancer predisposition linked to high birth weight

  3. Objectives • To define an epigenetic signature of risk of childhood leukemia in blood obtained at birth. • To discover an epigenetic signature of cancer risk in blood obtained from high birth weight babies.

  4. Hypothesis Environmental exposure during early embryonic life is able to imprint an epigenetic signature that can be used as a biomarker of exposure and susceptibility to cancer

  5. Why Epigenetics?

  6. Why Epigenetics? • Translocations frequently target epigenetic mechanisms • DNA methylation marks are commonly deregulated in ALL • Hot spots for translocations are common in CpG-rich regions

  7. Why Epigenetics? • Translocations frequently target epigenetic mechanisms MLL CBP MOZ MORF p300 Translocations frequently target chromatin modifiers HDACs DNMTs NCOR1 NCOR2 Fusion proteins are involved in the recruitment of silencing complexes

  8. Why Epigenetics? • DNA methylation marks are commonly deregulated in ALL MDR1, THSBS2, THSBS1, MYF3, ER, P15, CD10, c-ABL, p16, and p73 DNA methylation is deregulated in ALL overrepresentation of Wnt-related genes

  9. Why Epigenetics? • Hot spots for translocations are common in CpG-rich regions Tsai et al, Human Chromosomal Translocations at CpG sites and a Theoretical Basis of their Lineage and Stage Specificity. Cell 2008

  10. birth Epigenetic signature Epigenetic signature ? High birth weight ALL

  11. Approach • 200 archived blood spots (stratified according to birth weight) • DNA extraction, bisulfite modification, whole genome amplification • Epigenome analyses: Infinium 450K • Bioinformatics: epigenetic signature of high birth weight • Validation / Replication

  12. Perspectives • this proof of principle approach will provide a starting point from which to explore the association of multiple environmental exposures to an epigenetic profile linked to childhood cancer • the identification of reversible epigenetic alterations associated with environmental cues may have a strong impact in understanding and preventing cancer

  13. The I4C Epigenetics Working Group Yoshimi Inaba Murdoch Children’s Research Institute Carol H. Kasten National Children’s Study Sharon Savage National Cancer Institute Camilla Stoltenberg Norwegian Institute of Public Health Gabriella Tikellis Murdoch Children's Research Institute Joseph L. Wiemels University of California, San Francisco Nicholas C. Wong Murdoch Children's Research Institute Jia Chen Mount Sinai School of Medicine Jeff Craig Murdoch Children’s Research Institute Terence Dwyer Murdoch Children’s Research Institute Zdenko Herceg International Agency for Research on Cancer Hector Hernandez-Vargas International Agency for Research on Cancer Rayjean J. Hung University of Toronto

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