2017 Progress Report: Center for Integrative Research on Childhood Leukemia and the Environment

EPA Grant Number: R836159
Center: Center for Integrative Research on Childhood Leukemia and the Environment - 2015
Center Director: Metayer, Catherine
Title: Center for Integrative Research on Childhood Leukemia and the Environment
Investigators: Metayer, Catherine
Institution: University of California - Berkeley
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: September 1, 2015 through August 31, 2019
Project Period Covered by this Report: September 1, 2016 through August 31,2017
Project Amount: $2,599,999
RFA: Children's Environmental Health and Disease Prevention Research Centers (2014) RFA Text |  Recipients Lists
Research Category: Health , Children's Health

Objective:

The overarching theme of the current research is to identify additional in utero chemical risk factors for childhood acute lymphoblastic leukemia in an ethnically diverse population, and to understand how chemicals increase risk via immunological, genetic, and epigenetic mechanisms. We will use state-of-the-art methods to measure in utero chemical exposures that are potential risk factors for childhood leukemia and to characterize the biological mechanisms by which these chemicals may act on the fetus to increase the risk of leukemia in human and animal studies.

Progress Summary:

Project 1 on immune function is making progress towards completion of the aims. About 95% of the biospecimens for children and mothers are now available and laboratory work to measure cytokines is ongoing. Methods have been refined to minimize the amount of blood to be used and laboratory techniques are being tested to maximize sensitivity of the tests. While waiting for new data, we have established the pipeline for the proposed statistical analyses. We also have completed complementary analyses using other surrogate markers of immune function at birth (mode of delivery) and in the early years of life (history of allergy). Our data confirmed that C-section, especially elective, is increasing the risk of childhood leukemia, likely because of the lack of immune priming with vaginal flora (Wang, et al., 2017). This is an important finding as more C-Section deliveries are being conducted, stressing the need to only perform C-sections when recommended. In a large meta-analysis, self-reported allergies were not associated with childhood leukemia risk, likely due to poor recall (submitted). This negative finding adds more weight for carrying biomarker studies to objectively characterize the child’s immune status, as proposed in Project 1.

Project 2 on fetal exposome is making progress towards completion of the aims. We developed methods for profiling small molecules and Cys34 adducts of human serum albumin (HSA) from archived newborn blood specimens (ANBS) and then measured these chemicals via UPLC-HRMS. After statistical filtering, several thousand small-molecule features were available for analysis. The bioinformatic workflow then was developed in our laboratory (Edmands, et al., 2017). Of the roughly 1000 prevalent small-molecule features that were tested, multivariate linear regression detected significant associations with ethnicity (three metabolites) and birth weight (15 metabolites) after adjusting for multiple testing (Petrick, et al., 2017). Finally, the adductomics methodology was modified to simplify extraction of HSA from ANBS, and currently is being validated with ANBS from 50 pairs of control children, half of whom had mothers who actively smoked during pregnancy and half whose mothers were nonsmokers.

Statistical analyses currently are being conducted using a combination of parametric statistics (paired Student’s t-statistic) and machine-learning algorithms (lasso and random forest) for selection of variables that discriminate between childhood leukemia cases and controls. Small-molecule features that are included in the list of discriminating variables are being targeted for annotation by matching of MS/MS spectra and comparisons with reference standards (Edmands, et al., 2017). In parallel analyses, we detected several targeted molecules that had been selected as putative causes of CL (metabolites of benzene and biomarkers of coffee). These targeted molecules are being tested to determine whether they are present at higher levels in CL cases. 

These novel data-driven (untargeted) approaches are important to discover new risk factors that are potentially hazardous or protective for childhood leukemia and are not otherwise identifiable with targeted methods.

Project 3 on methylation is making progress towards completion of the aims. About 95% of the biospecimens for children and mothers now are available and laboratory work to complete HM450K methylation assays is ongoing. While waiting for new data, we have continued analysis using existing data to address the study aims. We have assessed the genomic contribution both genome-wide and locally to known epigenetic markers of maternal smoking (cg05575921), and found that DNA methylation at this locus was lower (which is the direction indicating increased smoking) at birth in our leukemia cases compared to controls (Gonseth, et al., 2016). We also assessed maternal smoking and tumor genetic features of leukemia cells, finding that self-reported smoking was associated with numbers of deletions in leukemia cells in a dose-dependent fashion (de Smith, et al., 2017). This result also was corroborated by using DNA methylation of cg05575921 as a biomarker of maternal smoking. In addition, we have worked with our colleagues at the International Agency for Research on Cancer (Zdenko Herceg and Akram Ghantous) and the University of Melbourne (Richard Saffery) to discover and validate new DNA methylation markers at birth that predict future risk of leukemia. Finally, our research group also is heavily involved in a new field called “immunomethylomics,” which is the analysis of blood cell types by their DNA methylation patterns and how this influences biology and disease incidence and progression.

Methylation studies are important to not only identify novel biomarkers of exposures, but also to assess the contribution of genetic and epigenetic factors in the development of childhood leukemia. 

The (COTC - Core B) continues to be extremely active in translating the findings from CIRCLE and from other relevant research groups (such as the Childhood Leukemia International Consortium [CLIC]) to various audiences. The COTC aims to improve pediatric environmental health literacy amongst the clinical audiences by organizing and giving presentations and symposia including at the Pediatric Academic Societies, the annual Children with Cancer UK conference, the University of Hawaii Pediatric Grand Rounds, UCSF Pediatric Malignancies Program, and the UCSF Center for Tobacco Control Research and Education. Also, we partnered with the California EPA, Office of Environmental Health Hazard Assessment and the Western States PEHSU to produce a children’s environmental health symposium in Sacramento in April 2017 entitled Environmental Justice and Children. It was well attended both in-person and online by more than 200 participants.

The Story Of Health (SOH) E-book continues to be successful. During the SOH's first 2 years online, there have been more than 6,000 registrations for physician, nurse, and health educator continuing education (CE) credits, representing in excess of 10,000 hours of CE credits to be awarded by the CDC. We have developed a low literacy version of the SOH, in an innovative comic book format in both English and Spanish, for use in our various anticipated programs. These will be used in our outreach programs, particularly in our trainings for Promotoras de Salud. The COTC also has produced an innovative “shadow puppet theater” short video titled “Love in the Time of Toxicants.” This provides an alternative format for introducing the ideas in the SOH materials for a general community audience. It is available in English and Spanish and has been well received in the United States as well as Mexico (Improving Environmental Health Literacy of Young Adults | Western States PEHSU Exit ).

The Mouse Model Facility Core C has worked with other CIRCLE investigators to identify chemicals to be tested on the leukemia prone-mouse model (i.e., polychlorinated biphenyls [PCBs], polyaromatic hydrocarbons [PAHs], cypermethrin and permethrin insecticides). The first experiments with PCBs are progressing well, and biospecimens were sent to Project 1 (cytokines) and Project 3 (methylation) researchers for respective laboratory assays.  

Future Activities:

Core B-COTC will continue to promote environmental health literacy to clinicians and targeted audiences such as Latino families, using innovative translation tools such as the comic book, and the updated version of the SOH E-book. Projects 1, 2, and 3 will continue laboratory work to characterize the cytokine profile, exposome/adductome, and methylation profile, respectively, and will continue to analyze the data, while developing statistical methods to better fit the complexity of multi-dimensional data. Another emphasis will be on integrating analyses from all projects. Core C will continue to conduct mouse model experiments to test leukemogenic potential of selected chemicals, and provide biospecimens for Project 1 (cytokines assays) and 3 (methylation assays).

References:

 Wang R, Wiemels JL, Metayer C, Morimoto L, Francis SS, Kadan-Lottick N, DeWan AT, Zhang Y, Ma X. Cesarean section and risk of childhood acute lymphoblastic leukemia in a population-based, record linkage study in California. American Journal of Epidemiology 2017;185(2):96-105.

Petrick L, Edmands W, Schiffman C, Grigoryan H, Perttula K, Yano Y, Dudoit S, Whitehead T, Metayer C, Rappaport S. An untargeted metabolomics method for archived newborn dried blood spots in epidemiologic studies. Metabolomics 2017 (in press).

Edmands WM, Petrick LM, Barupal DK, Scalbert A, Wilson M, Wickliffe J, Rappaport SM. compMS2Miner: an automatable metabolite identification, visualization and data-sharing R package for high-resolution LC-MS datasets. Analytical Chemistry 2017;89(7):3919-3928.

Gonseth S, Roy R, Houseman EA, de Smith AJ, Zhou M, Lee ST, Nusslé 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.

de Smith AJ, Kaur M, Gonseth S, Endicott AA, Selvin S, Zhang L, Roy R, Shao X, Hansen HM, Kang AY, Walsh KM, Dahl GV, McKean-Cowdin R, Metayer C, Wiemels JL. Correlates of prenatal and early-life tobacco smoke exposure and frequency of common gene deletions in childhood acute lymphoblastic leukemia. Cancer Research 2017;77(7):1674-1683.

Gonseth S, de Smith AJ, Roy R, Zhou M, Lee ST, Shao X, Ohja J, Wrensch MR, Walsh KM, Metayer C, Wiemels JL. Genetic contribution to variation in DNA methylation at maternal smoking-sensitive loci in exposed neonates. Epigenetics 2016;11(9):664-673.


Journal Articles: 23 Displayed | Download in RIS Format

Other center views: All 25 publications 23 publications in selected types All 23 journal articles
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Journal Article Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. Small-magnitude effect sizes in epigenetic end points are important in children's environmental health studies: the Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. R836159 (2018)
R835436 (2017)
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  • Journal Article de Smith AJ, Kaur M, Gonseth S, Endicott A, Selvin S, Zhang L, Roy R, Shao X, Hansen HM, Kang AY, Walsh KM, Dahl GV, McKean-Cowdin R, Metayer C, Wiemels JL. Correlates of prenatal and early-life tobacco smoke exposure and frequency of common gene deletions in childhood acute lymphoblastic leukemia. Cancer Research 2017;77(7):1674-1683. R836159 (2017)
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  • Journal Article Edmands WMB, Petrick LM, Barupal DK, Scalbert A, Wilson MJ, Wickliffe JK, Rappaport SM. compMS2Miner:an automatable metabolite identification, visualization, and data-sharing R package for high-resolution LC-MS data sets. Analytical Chemistry 2017;89(7):3919-3928. R836159 (2017)
    R836159C002 (2017)
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  • Journal Article Felix JF, Joubert BR, Baccarelli AA, Sharp GC, Almqvist C, Annesi-Maesano I, Arshad H, Baiz N, Bakermans-Kranenburg MJ, Bakulski KM, Binder EB, Bouchard L, Breton CV, Brunekreef B, Brunst KJ, Burchard EG, Bustamante M, Chatzi L, Cheng Munthe-Kaas M, Corpeleijn E, Czamara D, Dabelea D, Davey Smith G, De Boever P, Duijts L, Dwyer T, Eng C, Eskenazi B, Everson TM, Falahi F, Fallin MD, Farchi S, Fernandez MF, Gao L, Gaunt TR, Ghantous A, Gillman MW, Gonseth S, Grote V, Gruzieva O, Haberg SE. Cohort profile: Pregnancy And Childhood Epigenetics (PACE) Consortium. International Journal of Epidemiology 2018;47(1):22-23u. R836159 (2018)
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  • Journal Article Giddings BM, Whitehead TP, Metayer C, Miller MD. Childhood leukemia incidence in California: high and rising in the Hispanic population. Cancer 2016;122(18):2867-2875. R836159 (2017)
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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. R836159 (2017)
    R836159 (2018)
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  • Journal Article Gonseth S, de Smith AJ, Roy R, Zhou M, Lee S-T, Shao X, Ohja J, Wrensch MR, Walsh KM, Metayer C, Wiemels JL. Genetic contribution to variation in DNA methylation at maternal smoking-sensitive loci in exposed neonates. Epigenetics 2016;11(9):664-673. R836159 (2017)
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  • Journal Article Kaur M, de Smith AJ, Selvin S, Zhang L, Cunningham M, Kang MW, Hansen HM, Cooper RM, McKean-Cowdin R, Wiemels JL, Metayer C. Tobacco smoke and Ras mutations among Latino and non-Latino children with acute lymphoblastic leukemia. Archives of Medical Research 2016;47(8):677-683. R836159 (2018)
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  • Journal Article Metayer C, Dahl G, Wiemels J, Miller M. Childhood leukemia: a preventable disease. Pediatrics 2016;138 (Suppl 1):S45-S55. R836159 (2017)
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  • Journal Article Miller MD, Valenti M, Schettler T, Tencza B. A multimedia e-book — A story of health: filling a gap in environmental health literacy for health professionals. Environmental Health Perspectives 2016;124(8):A133-A136. R836159 (2017)
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  • Journal Article Miller MD, Valenti M, Schettler T, Tencza B. A story of health: filling a gap in environmental health literacy for health professionals. San Francisco Medicine, Journal of San Francisco Medical Society 2016;89(10):20-24 (Reprinted and edited with permission from Environmental Health Perspective). R836159 (2018)
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  • Journal Article Milne E, Greenop KR, Petridou E, Bailey HD, Orsi L, Kang AY, Baka M, Bonaventure A, Kourti M, Metayer C, Clavel J. Maternal consumption of coffee and tea during pregnancy and risk of childhood ALL: a pooled analysis from the Childhood Leukemia International Consortium. Cancer Causes & Control 2018;29(6):539-550. R836159 (2018)
    R834511 (Final)
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  • Journal Article Orsi L, Magnani C, Petridou ET, Dockerty JD, Metayer C, Milne E, Bailey HD, Dessypris N, Kang AY, Wesseling C, Infante-Rivard C, Wunsch-Filho V, Mora AM, Spector LG, Clavel J. Living on a farm, contact with farm animals and pets, and childhood acute lymphoblastic leukemia: pooled and meta-analyses from the Childhood Leukemia International Consortium. Cancer Medicine 2018;7(6):2665-2681. R836159 (2018)
    R834511 (Final)
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  • Journal Article Petrick L, Edmands W, Schiffman C, Grigoryan H, Perttula K, Yano Y, Dudoit S, Whitehead T, Metayer C, Rappaport S. An untargeted metabolomics method for archived newborn dried blood spots in epidemiologic studies. Metabolomics 2017;13(3):27 (19 pp.). R836159 (2017)
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  • Journal Article Petridou ET, Georgakis MK, Erdmann F, Ma X, Heck JE, Auvinen A, Mueller BA, Spector LG, Roman E, Metayer C, Magnani C, Pombo-de-Oliveira MS, Ezzat S, Scheurer ME, Mora AM, Dockerty JD, Hansen J, Kang AY, Wang R, Doody DR, Kane E, Rashed WM, Dessypris N, Schüz J, Infante-Rivard C, Skalkidou A. Advanced parental age as risk factor for childhood acute lymphoblastic leukemia: results from studies of the Childhood Leukemia International Consortium. European Journal of Epidemiology 2018;33(10):965-976. R836159 (2018)
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  • Journal Article Sharp GC, Salas LA, Monnereau C, Allard C, Yousefi P, Everson TM, Bohlin J, XuZ, Huang RC, Reese SE, Xu CJ, Baiz N, Hoyo C, Agha G, Roy R, Holloway JW, Ghantous A, Merid SK, Bakulski KM, Kupers LK, Zhang H, Richmond RC, Page CM, Duijts L, Lie RT, Melton PE, Vonk JM, Nohr EA, Williams-DeVane C, Huen K, Rifas-Shiman SL, Ruiz-Arenas C, Gonseth S, Rezwan FI, Herceg Z, Ekstrom S, Croen L, Falahi F, Perron P, Karagas MR, Quraishi BM, Suderman M, Magnus MC, Jaddoe VWV, Taylor JA, Anderson D, Zhao S, Smit HA, Josey MJ, Bradman A, Baccarelli AA, Bustamante M, Haberg SE, Pershagen G, Hertz-Picciotto I, Newschaffer C, Corpeleijn E, Bouchard L, Lawlor DA, Maguire RL, Barcellos LF, Davey Smith G, Eskenazi B, Karmaus W, Marsit CJ, Hivert MF, Snieder H, Fallin MD, Melen E, Munthe-Kaas MC, Arshad H, Wiemels JL, Annesi-Maesano I, Vrijheid M, Oken E, Holland N, Murphy SK, Sorensen TIA, Koppelman GH, Newnham JP, Wilcox AJ, Nystad W, London SJ, Felix JF, Relton CL. Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium. Human Molecular Genetics 2017;26(20):4067-4085. R836159 (2018)
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  • Journal Article Wallace AD, Francis SS, Shao X, de Smith AJ, Walsh KM, Mckean-Cowdin R, Ma X, Dahl G, Barcellos LF, Wiemels JL, Metayer C. A germ-line deletion of APOBEC3B does not contribute to subtype-specific childhood acute lymphoblastic leukemia etiology. Haematologica 2018;103(1):e29-e31. R836159 (2018)
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  • Journal Article Wallace AD, Francis SS, Ma X, McKean-Cowdin R, Selvin S, Whitehead TP, Barcellos LF, Kang AY, Morimoto L, Moore TB, Wiemels JL, Metayer C. Allergies and childhood acute lymphoblastic leukemia: a case-control study and meta-analysis. Cancer Epidemiology, Biomarkers and Prevention 2018;27(10):1142-1150. R836159 (2018)
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  • Journal Article Walsh KM, Whitehead TP, de Smith AJ, Smirnov IV, Park M, Endicott AA, Francis SS, Codd V, ENGAGE Consortium Telomere Group, Samani NJ, Metayer C, Wiemels JL. Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers. Carcinogenesis 2016;37(6):576-582. R836159 (2018)
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  • Journal Article Wang R, Wiemels JL, Metayer C, Morimoto L, Francis SS, Kadan-Lottick N, DeWan AT, Zhang Y, Ma X. Cesarean section and risk of childhood acute lymphoblastic leukemia in a population-based, record-linkage study in California. American Journal of Epidemiology 2017;185(2):96-105. R836159 (2017)
    R836159 (2018)
    R836159C001 (2017)
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  • Journal Article Wang R, Metayer C, Morimoto L, Wiemels JL, Yang J, DeWan AT, Kang A, Ma X. Parental age and risk of pediatric cancer in the offspring: a population-based record-linkage study in California. American Journal of Epidemiology 2017;186(7):843-856. R836159 (2018)
    R834511 (Final)
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  • Journal Article Whitehead TP, Metayer C, Wiemels JL, Singer AW, Miller MD. Childhood leukemia and primary prevention. Current Problems in Pediatric and Adolescent Health Care 2016;46(10):317-352. R836159 (2017)
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  • Journal Article Wiemels JL, Walsh KM, de Smith AJ, Metayer C, Gonseth S, Hansen HM, Francis SS, Ojha J, Smirnov I, Barcellos L, Xiao X, Morimoto L, McKean-Cowdin R, Wang R, Yu H, Hoh J, DeWan AT, Ma X. GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21. Nature Communications 2018;9(1):286 (8 pp.). R836159 (2018)
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  • Progress and Final Reports:

    Original Abstract
  • 2016 Progress Report
  • 2018 Progress Report
  • 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