Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE)

EPA Grant Number: R834511
Center: Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE)
Center Director: Buffler, Patricia
Title: Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE)
Investigators: Buffler, Patricia , Barcellos, Lisa , Chokkalingam, Anand , Dahl, Gary , Kyle, Amy , Metayer, Catherine , Miller, Mark , Rappaport, Stephen M. , Selvin, Steve , Wiemels, Joe , Zhang, Luoping
Current Investigators: Metayer, Catherine
Institution: University of California - Berkeley , Stanford University , University of California - San Francisco
Current Institution: University of California - Berkeley
EPA Project Officer: Louie, Nica
Project Period: September 25, 2009 through September 24, 2015
Project Amount: $3,704,598
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

The overarching goal of this Children’s Center is to examine the interplay of environmental, genetic and epigenetic (DNA/gene expression) factors related to the risk of leukemia in children, with a focus on potentially carcinogenic common chemicals, i.e. pesticides, tobacco-related carcinogens, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs/flame retardants). We plan to (1) evaluate pre- and postnatal environmental exposures, and improve exposure assessment, building upon the Northern California Childhood Leukemia Study using existing home dust samples and biospecimens; (2) examine environmental and genetic influences for distinct leukemia subtypes defined by molecular, chromosomal, and epigenetic markers; and (3) disseminate findings and advance public health by providing information that supports action and policy changes by advocates and individual steps to improve children's environmental health.

Approach:

We propose a series of projects progressing from a “conventional” genetic epidemiology study, to state-of-the-art exposure assessment, and the investigation of epigenetic mechanisms associated with exposures and leukemia risk. Specifically, Project 1 (Childhood Leukemia International Consortium Studies) will pool interview and genotyping data from approximately 14 case-control studies worldwide. We will examine the association between parental smoking and home pesticide use during different periods, gene variants for the way cells metabolize foreign substances and risk of childhood leukemia subtypes. In Project 2 (Exposure Assessment for Childhood Leukemia), we will measure nicotine, PCBs, and PBDEs in diagnostic serum samples obtained from ~250 childhood leukemia cases and determine correlations between analyte levels in serum and house dust. Using newly developed methods by UC Berkeley, we will profile cysteinyl adducts of human serum albumin (HSA) in blood samples collected at diagnosis and at birth (newborn dried blood spot [DBS]) to quantify internal doses of chemical exposures. Project 3 (Prenatal Exposures, DNA Methylation, and Childhood Leukemia) will investigate mechanisms linking environmental factors and a biological imprint within leukemia cells, i.e., DNA methylation (an epigenetic gene modification) in gene promoters. We will establish the role of DNA methylation as a biomarker of early biological effects from environmental exposures as well as a precursor to leukemia, and will explore the use of methylation biomarkers in the early detection and prediction of leukemia using newborn DBS from the general population. The Research Translation and Community Outreach (RTCO) Core will connect with audiences external to those involved in scientific research or clinical practice, including communities interested in advancing children's environmental health. The RTCO will translate the scientific findings and methodological advances in ways that increase understanding and enhance capacity for meaningful change, including public policy development. The Administrative Core will provide centralized scientific, administrative, and data management support to implement and foster synergy between the Center Projects and the RTCO Core.

Expected Results:

Expected results include identifying time-specific chemical exposures and genetic variants associated with subtypes of childhood leukemia, assessing importance of exposures to persistent contaminants that may cause leukemia, based upon analysis of house dust and blood samples, and developing a panel of methylation markers (epigenetic DNA markers) to be utilized in future biomonitoring, risk stratification, and epidemiology studies. We hope to advance public health by providing information that can support actions to improve children's environmental health.


Journal Articles: 13 Displayed | Download in RIS Format

Other center views: All 52 publications 13 publications in selected types All 13 journal articles
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Journal Article Bailey HD, Fritschi L, Infante-Rivard C, Glass DC, Miligi L, Dockerty JD, Lightfoot T, Clavel J, Roman E, Spector LG, Kaatsch P, Metayer C, Magnani C, Milne E, Polychronopoulou S, Simpson J, Rudant J, Sidi V, Rondelli R, Orsi L, Kang AY, Petridou E, Schuz J. Parental occupational pesticide exposure and the risk of childhood leukemia in the offspring: findings from the Childhood Leukemia International Consortium. International Journal of Cancer 2014;135(9):2157-2172. R834511 (2014)
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  • Journal Article de Smith AJ, Walsh KM, Ladner MB, Zhang S, Xiao C, Cohen F, Moore TB, Chokkalingam AP, Metayer C, Buffler PA, Trachtenberg EA, Wiemels JL. The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia. Blood 2014;123(16):2497-2503. R834511 (2013)
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  • Journal Article Gonseth S, Roy R, Houseman EA, de Smith AJ, Zhou M, Lee ST, Nussle S, Singer AW, Wrensch MR, Metayer C, Wiemels JL. Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes. Epigenetics 2015;10(12):1166-1176. R834511 (2014)
    R836159 (2017)
    R836159C003 (2016)
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  • Journal Article Lee S-T, Xiao Y, Muench MO, Xiao J, Fomin ME, Wiencke JK, Zheng S, Dou X, de Smith A, Chokkalingam A, Buffler P, Ma X, Wiemels JL. A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network. Nucleic Acids Research 2012;40(22):11339-11351. R834511 (2012)
    R834511 (2013)
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  • Journal Article Lee S-T, Muench MO, Fomin ME, Xiao J, Zhou M, de Smith A, Martin-Subero JI, Heath S, Houseman EA, Roy R, Wrensch M, Wiencke J, Metayer C, Wiemels JL. Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures. Nucleic Acids Research 2015;43(5):2590-2602. R834511 (2014)
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  • Journal Article Metayer C, Milne E, Dockerty JD, Clavel J, Pombo-de-Oliveira MS, Wesseling C, Spector LG, Schuz J, Petridou E, Ezzat S, Armstrong BK, Rudant J, Koifman S, Kaatsch P, Moschovi M, Rashed WM, Selvin S, McCauley K, Hung RJ, Kang AY, Infante-Rivard C. Maternal supplementation with folic acid and other vitamins before and during pregnancy and risk of leukemia in the offspring: a Childhood Leukemia International Consortium (CLIC) study. Epidemiology 2014;25(6):811-822. R834511 (2013)
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  • Journal Article Milne E, Greenop KR, Metayer C, Schuz J, Pertridou E, Pombo-de-Oliveira MS, Infante-Rivard C, Roman E, Dockerty JD, Spector LG, Koifman S, Orsi L, Rudant J, Dessypris N, Simpson J, Lightfoot T, Kaatsch P, Baka M, Faro A, Armstrong BK, Clavel J, Buffler PA. Fetal growth and childhood acute lymphoblastic leukemia: findings from the Childhood Leukemia International Consortium (CLIC). International Journal of Cancer 2013;133(12):2968-2979. R834511 (2013)
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  • Journal Article Whitehead TP, Brown FR, Metayer C, Park J-S, Does M, Petreas MX, Buffler PA, Rappaport SM. Polybrominated diphenyl ethers in residential dust:Sources of variability. Environment International 2013;57-58:11-24. R834511 (2013)
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  • Journal Article Whitehead TP, Crispo Smith S, Park JS, Petreas MX, Rappaport SM, Metayer C. Concentrations of persistent organic pollutants in California children’s whole blood and residential dust. Environmental Science & Technology 2015;49(15):9331-9340. R834511 (2014)
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  • Journal Article Xiao J, Lee S-T, Xiao Y, Ma X, Houseman EA, Hsu L-I, Roy R, Wrensch M, de Smith AJ, Chokkalingam A, Buffler P, Wiencke JK, Wiemels JL. PTPRG inhibition by DNA methylation and cooperation with RAS gene activation in childhood acute lymphoblastic leukemia. International Journal of Cancer 2014;135(5):1101-1109. R834511 (2014)
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  • Journal Article Li H, Grigoryan H, Funk WE, Lu SS, Rose S, Williams ER, Rappaport SM. Profiling Cys34 adducts of human serum albumin by fixed-step selected reaction monitoring. Molecular & Cellular Proteomics 2011;10(3):M110.004606. R834511 (2013)
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  • Journal Article Metayer C, Milne E, Clavel J, Infante-Rivard C, Petridou E, Taylor M, Schuz J, Spector LG, Dockerty JD, Magnani C, Pombo-de-Oliveira MS, Sinnett D, Murphy M, Roman E, Monge P, Ezzat S, Mueller BA, Scheurer ME, Armstrong BK, Birch J, Kaatsch P, Koifman S, Lightfoot T, Bhatti P, Bondy ML, Rudant J, O'Neill K, Miligi L, Dessypris N, Kang AY, Buffler PA. The Childhood Leukemia International Consortium. Cancer Epidemiology 2013;37(3):336-347. R834511 (2013)
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  • Journal Article Zhang L, Samad A, Pombo-de-Oliveira MS, Scelo G, Smith MT, Feusner J, Wiemels JL, Metayer C. Global characteristics of childhood acute promyelocytic leukemia. Blood Reviews 2015;29(2):101-125. R834511 (2014)
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  • 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

    Progress and Final Reports:

    2010 Progress Report
    2011 Progress Report
    2012 Progress Report
    2013 Progress Report
    2014 Progress Report
    Final Report

    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