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Prenatal Exposures, DNA Methylation & Childhood LeukemiaEPA Grant Number: R834511C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R834511
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE)
Center Director: Buffler, Patricia
Title: Prenatal Exposures, DNA Methylation & Childhood Leukemia
Investigators: Buffler, Patricia
Institution: University of California - Berkeley , Stanford University , University of California - San Francisco
EPA Project Officer: Louie, Nica
Project Period: September 24, 2009 through September 24, 2015
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Health
At the cellular level pediatric leukemias like other cancers are caused by genetic and epigenetic alterations. Distinct subtypes of cytogenetic abnormalities have been recognized in childhood ALL for many years and are cornerstones of leukemia patient management and more recently, epidemiology studies. Recent studies on the epigenetics of leukemia suggest that alterations including DNA methylation are common and potentially important features of childhood ALL. Our preliminary studies and those of others have shown that DNA methylation events in leukemia are complex. Some events are reflective of the normal developmental epigenetic programs and therefore the events simply mirror the normal biology of the progenitor population of cells that were transformed. Other events are acquired during the transformation process. Some may arise from early epigenetic aberrations resulting from environmental exposures and developmental abnormalities. In this project we will attempt to delineate the critical DNA methylation events in pediatric leukemias and furthermore define those influenced by the environment, particularly in the prenatal period. The development of a panel of exposure- and leukemia-related biomarkers is the goal, which could be utilized in future biomonitoring, risk stratification, and epidemiology studies. We will characterize the DNA methylation pattern of normal B-cell progenitors and a series of leukemia bone marrow samples (n=250) using a high dimension technology, to define the DNA methylation events critical in leukemia. Second, we will utilize the same technology to define the DNA methylation pattern at birth on same 250 leukemia cases and their case bloods using neonatal dried blood spot (DBS) DNA.
Using novel statistical techniques, we will associate DNA methylation patterns and individual genes to specific and quantitative data on environmental exposures including a chemical analysis of over 120 analytes in house dust, with repeat measurements at 150 houses, and an assessment of album in-chemical adducts in 200 subjects (from Project 2). Using this information we will validate a subset of the most informative (ie., leukemia - and environmental-associated) methylation markers using a distinct set of neonatal DBS that are part of the Northern California Childhood Leukemia Study and a new set of cards from the California Department of Public Health, and seek to understand the role of DNA methylation in gene-environment interaction in leukemia-associated DNA methylation at birth.
Supplemental Keywords:House dust, biomarkers, dried blood spot, exposure assessment, risk assessment, sensitive population, carcinogens, population, infants, children, genetic pre-disposition, genetic susceptibility, Hispanics, PAH, PCB, PBDE, nicotine, pesticides, public policy, decision making, community-based, public health, environmental epidemiology, genetics, toxicology, biostatistics, epigenetic, modeling, gene-environment interaction, measurement methods, California, international,
Main Center Abstract and Reports:R834511 Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE)
Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834511C001 Childhood Leukemia International Consortium Studies
R834511C002 Exposure Assessment for Childhood Leukemia
R834511C003 Prenatal Exposures, DNA Methylation & Childhood Leukemia