2018 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, 2017 through August 31,2018
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 (ALL) 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. Below is a summary for the progresses in each Core and Project. Overall, we estimate that we are above 50% completion, and anticipate to accelerate the pace of the laboratory work and statistical analyses now that 99% of biospecimens are available.

Progress Summary:

Project 1 on immune function is making progress towards completion of the aims. The biospecimens for the mother-child pairs are now available and laboratory work to measure cytokines in children has been completed. We have analyzed the cytokine profiles of 137 cases of childhood ALL and 499 matched control subjects. The cytokines included IL-1β, IL-4, IL-6, IL-8, IL-10, IL-12p70, GM-CSF, TNF- α, and VEGF. As we observed high correlations across the cytokines and were concerned about colinearity, we utilized the principle component approach to derive six components that are independent from each other. Since the first three components explained more than 72% of the variance, we decided to focus on these components. When we compared the components between cases and controls, both Components 1 and 3 were significantly associated with the risk of childhood ALL. While it is premature to draw conclusions at this point, it appears that our hypothesis regarding the role of immunomodulatory cytokines in leukemogenesis is supported by the current data. Biospecimens from the subjects in the California Childhood Leukemia Study (CCLS) will be tested next. While waiting for more cytokine data, our group continued to analyze epidemiologic and socio-demographic data from our linkage study.

Project 2 on fetal exposome is making progress towards completion of the aims for both the metabolomic and adductomic experiments. The small-molecule features have been measured and annotated in the archived newborn blood specimens (ANBS) from 400 childhood leukemia cases and matching controls from CCLS as proposed. Using the bioinformatics pipeline developed in this project for small molecules, over 800 common metabolic features were compared between ALL cases and controls. Feature selection pointed to potential roles of several lipids in the etiology of ALL, including linolenic and linoleic acids and phospholipids with 18:2 and eicosatetraenoic acid moieties. Significantly, many of the selected metabolites were highly associated with breastfeeding practice in children diagnosed with ALL after age 6, suggesting that particular nutrients in breast milk are protective for ALL. The method developed for characterization of HSA adduct features was validated with a set of 46 ANBS from control children, half with mothers who smoked during pregnancy and half with nonsmoking mothers. Using the bioinformatics pipeline and statistics package developed in this project, a total of 26 adducts were identified, and one HSA adduct feature (from reaction with cyanide) was highly predictive of smoking status (higher in children of smoking mothers). This is consistent with literature reports that cyanide levels are higher in blood of smokers than of nonsmokers and indicates that our adductomics methodology using a small amount of blood from the ANBS is appropriate for comparing CL cases to controls to find discriminating features. We are now applying the laboratory and statistical pipeline to the full set of 400 cases and 400 controls from the CCLS.

Project 3 on methylation is making progress towards completion of the aims. We have continued to analyze existing DNA methylation data on ANBS, and construct new datasets using updated DNA methylation arrays (Illumina HM850K). More samples are currently being analyzed at the laboratory and will be available for analyses in a couple of months. We have also participated in PACE Consortium (Pregnancy and Childhood Epigenetics) activities which involve the meta-analysis of our HM450K methylation data with many other groups also studying neonatal DNA methylation patterns caused by environmental and demographic variations among populations. Our work with colleagues at the International Agency for Research on Cancer on DNA methylation events that predict leukemia case status has resulted in several replicable DNA methylation biomarkers at birth that predict future leukemia risk. These marks include CpGs within the genes MGMT, HLA-B, ABR, and VTRNA2-1. We are further exploring potential DNA methylation gene X environment interactions, in particular for the MGMT gene which is a DNA repair gene, and HLA-B, which is a part of a complex of immune response genes. Our research group is also 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. We have continued work on optimizing our mouse model for leukemia and preparing relevant chemical dosing strategies. This work was completed for PCBs, and we have performed reduced representation bisulfite sequencing on pups from treated and untreated animals. Statistical analyses are underway.

The Administrative Core (Core A): continues to support the infrastructure and scientific direction of the Center. We completed the selection and acquisition of the biospecimens that were available at the CA biobank, and are in the process of upgrading the data linkage to meet our target sample size for mother-child pair specimens. Specimens are being used for all three Projects, ensuring sufficient overlap for future integration of the data generated on cytokines (Project 1), exposome and protein adducts (Project 2), and genetic/epigenetic (Project 3). The Community Outreach and Translation Core (COTC) has established a distinguished community advisory group that held its third meeting in February 2018. The Internal Advisory Committee continues to meet every two months to provide updates on all Cores and Projects, and to facilitate scientific interaction between CIRCLE investigators. We plan to hold the next External Advisory Committee meeting in early 2019.

The career development investigator is working closely with the leaders of all Cores and Projects. His main role this year was to ensure integration between projects (such as adductomic and epigenetic data) and shared biospecimens. He also is pursuing his own innovative research and submitted several grants. Dr. Whitehead was successfully awarded a new R24 grant, (with PI Catherine Metayer) where he is leading the work on examining the association between maternal stress during pregnancy and child telomere length, and his/her subsequent risk of leukemia. Dr. Whitehead collaborated with the tobacco prevention program at University of California at San Francisco (UCSF) to design an intervention study to reduce exposure to third-hand tobacco, using dust sampling as objective measures (grant under review).

As indicated in an email to Nica Louie on December 19th, 2017, Joe Wiemels (Leader of Project 3 and Co-Investigator of Project 1) transitioned his primary affiliation from UCSF to USC effective January 1st, 2018. Because Dr. Wiemels has continued to keep an affiliation at UCSF, he was able to continue to serve as the EPA subcontract PI at UCSF for these projects for the past year (Year 3 of the grant), working closely with our other UCSF-based investigator Scott Kogan (who is the current leader of the CIRCLE mouse modeling Core to support Aims in Projects 1 and 3, and who has overseen work done at UCSF during Joe's transition to USC). We will continue to conduct the EPA-supported work at UCSF in Year 4, and therefore we propose to list Dr. Scott Kogan as the UCSF subaward PI for the EPA portion (note that Joe Wiemels will be the USC subaward PI for the NIEHS portion of the grant). Both Drs. Kogan and Wiemels will be in regular contact by email and phone to coordinate the work for Projects 1 and 3. This change will be seamless as (i) we will be able to accomplish our aims, (ii) there is no change in key personnel, and (iii) the change is cost neutral.

The Community Outreach and Translation Core (COTC, Core B): This core 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, UCSF Pediatric Malignancies Program, and the International Society for Environmental Epidemiology. Also, we partnered with the California EPA, Office of Environmental Health Hazard Assessment and the Western States Pediatric Environmental Health Specialty Unit (PEHSU) to produce a children's environmental health symposium in Sacramento in April 2017 on ''Environmental Justice and Children.'' This was the first ever symposium to focus specifically on this issue and is relevant to our CIRCLE COTC aims as many of the environmental justice community exposures of concern are also linked to childhood leukemia risk. Dr. Miller also joined with others to create a work group to develop changes to National Cancer Institute (NCI) materials to address the potential roles of environmental exposures in childhood cancer and include actions that might reduce risks.

The Story Of Health (SOH) e-book continues to be successful. We have continued working with the Western States PEHSU and other partners and in fall 2017 released the fourth chapter of the Story of Health (SOH) multimedia eBook (on infertility and reproductive health). So far, the SOH has had over 8,800 registrations for physician, nurse, and health educator continuing education (CE) credit representing approximately 14,000 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 (lay health workers). The COTC has produced also 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 Story of Health materials for a general community audience. It is available in English and Spanish and has been well received in the US as well as Mexico (https://wspehsu.ucsf.edu/projects/improving-environmental-health-literacy-young-adults/). The materials described above were released and are available in Spanish and specifically address the needs of the Latino community. They have been used in numerous workshops presented to parents, promotores de salud (lay health workers), child care workers, and at health fairs.

The Mouse Model Facility (Core C): This core has worked with CIRCLE investigators to identify chemicals to be tested on the leukemia prone-mouse model. The PCB models have been completed. Our results show that for the PCB models we studied, under the exposure regimen and in the environment of a specific pathogen-free facility, we did not observe an impact of prenatal PCB exposure on disease. Our experience with the PCB cohorts has enabled us to refine our exposure studies by using an alternative mouse model more prone to develop leukemia, and we are moving forward with the testing of additional agents. The Core is currently exposing pregnant mice to tobacco in the form of third hand smoke, to the PAH dibenz[a,h]anthracene, and to the insecticides Permethrin and Cypermethrin.

Future Activities:

Core A will continue to provide infrastructure support and scientific direction to the other Cores and Projects. 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, and videos. Projects 1, 2, and 3 will continue the laboratory work to characterize 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).


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)
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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)
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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)
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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)
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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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  • Relevant Websites:

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

    Western States PEHSU Exit

    Love in the Time of Toxicants Exit

    Improving Environmental Health Literacy of Young Adults Exit

    Progress and Final Reports:

    Original Abstract
  • 2016 Progress Report
  • 2017 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