Parent Title:
Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE)
Grant Number:
Principal Investigator:
Metayer, Catherine (PI of Parent Grant CIRCLE); Wiemels, Joseph (Leader of Project 3)
Institution:
University of California, Berkeley
Most Recent Award Year:
2015
Lifestage of Participants:
Exposure:
Prenatal
Assessment:
Youth (1-14 years)
Exposures:
Other:
Chemical, dietary, and immune factors
Health Outcomes:
Cancer Outcomes:
Childhood acute lymphoblastic leukemia
Biological Sample:
Newborn dried blood spots; Bone marrow
Epigenetic Mechanisms Studied:
DNA Methylation
Abstract:
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 our 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. We will address this knowledge gap in the current proposal. First, we 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, we 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, we 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 (our target cell population), as well as on leukemogenesis.
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Related NIEHS-Funded Study Populations
California Childhood Leukemia Study (CCLS)
Principal Investigator:
Metayer, Catherine (Buffler, Patricia)
| Study Population Page Study Population c79
Institution:
University of California, Berkeley
Location:
California
Number of Participants::
3,523 (2,213 cases and 1,310 controls)
Brief Description::
This is a population-based case-control study to examine the relationship between environmental exposures, genetic factors, and childhood leukemia. The study has undergone multiple phases of enrollment since 1995 and and now includes over 2,000 leukemia cases.