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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

I4C Epigenetics Working Group

Barcelona, September 2011

proposal
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
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.
hypothesis
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

why epigenetics1
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
why epigenetics2
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

why epigenetics3
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

why epigenetics4
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

slide11

birth

Epigenetic signature

Epigenetic signature ?

High birth weight

ALL

approach
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
perspectives
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
the i4c epigenetics working group
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