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

• 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

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 Epigenetics?

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 Epigenetics?

• Translocations frequently target epigenetic mechanisms

Translocations frequently target chromatin modifiers

MLLCBPMOZMORFp300

Fusion proteins are involved in the recruitment of silencing complexes

HDACsDNMTsNCOR1NCOR2

Why Epigenetics?

• DNA methylation marks are commonly deregulated in ALL

DNA methylation is deregulated in ALL

MDR1, THSBS2, THSBS1, MYF3, ER, P15, CD10, c-ABL, p16, and p73

overrepresentation of Wnt-related genes

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

birth

ALL

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• 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 GroupJia 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

Yoshimi Inaba

Murdoch Children’s Research Institute

Carol H. Kasten

National Children’s Study

Sharon Savage

National Cancer Institute

Camilla StoltenbergNorwegian Institute of Public Health Gabriella TikellisMurdoch Children's Research Institute

Joseph L. WiemelsUniversity of California, San Francisco Nicholas C. WongMurdoch Children's Research Institute