Prenatal Exposures, Constitutive Genetics, DNA Methylation & Childhood Leukemia

EPA Grant Number: R836159C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R836159
(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 - 2015
Center Director: Metayer, Catherine
Title: Prenatal Exposures, Constitutive Genetics, DNA Methylation & Childhood Leukemia
Investigators: Wiemels, Joseph , Metayer, Catherine , Segal, Mark , Whitehead, Todd , de Smith, Adam
Institution: University of California - San Francisco , University of California - Berkeley
EPA Project Officer: Louie, Nica
Project Period: September 1, 2015 through August 31, 2019
RFA: Children's Environmental Health and Disease Prevention Research Centers (2014) RFA Text |  Recipients Lists
Research Category: Health , Children's Health

Objective:

Specific Aim 1: Use genome-wide DNA single nucleotide polymorphism (SNP) data to assess the impact of genetic variation on DNA methylation.

Specific Aim 2: Investigate the effects of both genetic and environmental factors on DNA methylation and risk of acute lymphoblastic leukemia (ALL). 

Specific Aim 3: Assess the effects of particular in utero chemical exposures on DNA methylation in pre-B cells and leukemogenesis.  

Approach:

In this project, investigators will address the knowledge gap regarding the combination of environmental and genetic causes of variation in DNA methylation. First, they will use genome-wide DNA single nucleotide polymorphism (SNP) data to assess the impact of genetic variation on DNA methylation among 200 acute lymphoblastic leukemia (ALL) cases and 400 controls from the California Mother-Child Birth Cohort. A second set of 200 ALL cases and 400 controls of CCLS subjects will be used for replication and meta-analysis. As a second aim, investigators will use the same two case/control sets to investigate the effects of both genetic and environmental factors on DNA methylation and ALL risk. Chemical risk factors for ALL identified in Project 2 during the next funding cycle, chemical risk factors for ALL that were previously identified by our research group, and immune risk factors for ALL identified in Project 1 will be used in the proposed Project 3 statistical analysis. The biospecimens from 400 cases and 800 controls (two sets together) used in Project 3 will completely overlap with those assessed for cytokines in Project 1 and those assessed for protein adducts and small molecules in Project 2. Finally, investigators will use a mouse model that recapitulates the features of human childhood leukemia to directly assess the effects of particular in utero chemical exposures on DNA methylation in pre-B cells (the target cell population), as well as on leukemogenesis. 

Rationale:

Pre-B cell leukemia is the most common cancer in children, and though treatable in most cases, the disease leads to long-term morbidity. Preventing leukemia requires an understanding of its causes. In the previous funding cycle, we found that childhood leukemia tumor cells are profoundly altered from pre-B cell precursors with regards to DNA methylation; i.e., methylation of fully 10% of CpG sites is altered during leukemogenesis. Environmental risk factors, including chemical factors (polycyclic aromatic hydrocarbons) and dietary factors (folic acid), which were found to impact childhood leukemia risk in a previous epidemiology study (California Childhood Leukemia Study, CCLS), also affect DNA methylation. Genetic risk factors impact DNA methylation locally and genome-wide. While researchers have increasingly focused on the environmental and genetic causes of variation in DNA methylation, few have accounted for the impact of the combination of the two factors. 

Publications and Presentations:

Publications have been submitted on this subproject: View all 3 publications for this subprojectView all 12 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 3 journal articles for this subprojectView all 10 journal articles for this center

Relevant Websites:

http://circle.berkeley.edu/

Progress and Final Reports:

2016 Progress Report
2017 Progress Report


Main Center Abstract and Reports:

R836159    Center for Integrative Research on Childhood Leukemia and the Environment - 2015

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R836159C001 In Utero Chemical Exposures, Immune Status, and Childhood Leukemia
R836159C002 Identifying In Utero Exposures that are Risk Factors for Childhood Leukemia
R836159C003 Prenatal Exposures, Constitutive Genetics, DNA Methylation & Childhood Leukemia