Grantee Research Project Results
2010 Progress Report: Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE)
EPA Grant Number: R834511Center: 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 (CIRCLE)
Investigators: Buffler, Patricia , Rappaport, Stephen M. , Kyle, Amy , Chokkalingam, Anand , Metayer, Catherine , Dahl, Gary , Wiemels, Joe , Barcellos, Lisa , Zhang, Luoping , Miller, Mark , Selvin, Steve
Current Investigators: Metayer, Catherine
Institution: University of California - Berkeley , University of California - San Francisco , Stanford University
Current Institution: University of California - Berkeley
EPA Project Officer: Hahn, Intaek
Project Period: September 25, 2009 through September 24, 2015
Project Period Covered by this Report: September 25, 2009 through September 24,2010
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 , Human Health
Objective:
The proposed new Children’s Environmental Health Center based at the University of California, Berkeley is designed to examine the effects of in utero and early life exposure to potentially carcinogenic chemicals present in homes (i.e., pesticides, tobacco-related contaminants, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs), genetic and epigenetic factors and their interplay in the development of childhood leukemia. The proposed Center, referred to as Center for Interdisciplinary Research on Childhood Leukemia and the Environment (CIRCLE) includes three Research Projects and two Cores.
RD834511C001: Childhood Leukemia International Consortium Studies
Childhood Leukemia International Consortium Studies will identify the exposures to the most relevant time periods and childhood leukemia subtypes and identify important genetic polymorphisms that can modify the association between childhood leukemia and parental tobacco smoking or home pesticide exposure by pooling data from 19 studies worldwide.
RD834511C002: Exposure Assessment for Childhood Leukemia
Exposure Assessment for Childhood Leukemia will assess carcinogen exposures, based upon analysis of house dust and blood specimens, with special interest in tobacco-related contaminants, PCBs, and PBDEs.
RD834511C003: Prenatal Exposures, DNA Methylation, & Childhood Leukemia
Prenatal exposures, DNA Methylation, & Childhood Leukemia will provide a clearer understanding of the association between parental smoking, pesticides, PCBs, PBDEs exposures and DNA methylation patterns in childhood leukemia, using neonatal bloods.
Progress Summary:
RD834511C001: Childhood Leukemia International Consortium Studies
Specific Aim 1: Pool data elements collected from 14 CLIC case-control studies in 10 countries.
More than 40 participants attended the 2010 CLIC Annual Meeting held in Boston, October 19-20 (the meeting minutes are available at http://clic.berkeley.edu Exit). The work proposed under the current award was presented at the meeting and well received. Following the meeting, the CLIC Management Group (chaired by Pr. Buffler, Director of CIRCLE) held regular (monthly and bimonthly) conference calls to discuss issues related to data pooling and data directories, progress on proposed pooled analyses, new applications for CLIC individual and study memberships, and organization of the CLIC annual meeting.
The procedures for requesting data have been revised by the Data Pooling Core Logistics Group and the next call for Expressions of Interest (EOI) for CLIC PIs to propose pooled analyses is June 1, 2011. The lead roles for pooled analyses in the current award are presented in Table 1. The affiliated institution of Dr. Helen Bailey is the Telethon Institute for Child Health Research, West Perth, Australia. Dr. Bailey will be conducting the pooled analyses at the International Agency for Research on Cancer (IARC) as part of her post-doc position under the supervision of Dr. Joachim Schuz (Head, Section of Environment and Radiation, IARC).
The survey to assess quality and completeness of cytogenetic data in CLIC studies is under review by two CLIC molecular biology members (Drs. Zhang and Pombo-de-Oliveira), and will be circulated to all CLIC PIs. Additionally, a survey of available genetic data and biospecimens is under way.
Table 1 |
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Pooled analyses |
Lead Investigator |
Institution |
Status of Data Request |
Parental smoking, metabolizing genes, and risk of ALL |
Infante-Rivard C. |
McGill University, Montreal, Quebec, Canada |
EOI approved - Data requested in April 2011 |
Parental smoking, metabolizing genes and risk of AML and APL |
Metayer C. |
UC Berkeley, USA |
EOI in June 2011 - Data request expected August 2011 |
Home pesticide use and risk of ALL & AML |
Bailey H. |
IARC, France |
EOI in June 2011 – Data request expected August 2011 |
Geographical distribution of AML, APL and other cytogenetic subtypes |
Zhang L. |
UC Berkeley, USA |
EOI in June 2011 - Data request expected August 2011 |
Geographical distribution of ALL cytogenetic subtypes |
Pombo-de-Oliveira M. (to be confirmed) |
National Cancer Institute, Rio de Janeiro, Brazil |
EOI to be developed |
Specific Aim 2: Conduct descriptive analyses to assess geographical differences in the frequency of leukemia subtypes defined by age, immunophenotype and cytogenetics, and assess possible sources for geographical differences.
No activities were conducted on this aim in Year 2 (waiting to obtain data).
Specific Aim 3: Assess the association between maternal/paternal smoking or home pesticide exposures and childhood leukemia during different time periods (prenatal, during pregnancy, and postnatal) stratified by histologic, immunophenotypic, and cytogenetic subtypes.
No activities were conducted on this aim in Year 2 (waiting to obtain data).
Specific Aim 4: Examine the influence of genetic variation on the association between parental smoking or home pesticide exposures and childhood leukemia by histologic, immunophenotypic and cytogenetic subtypes.
No activities were conducted on this aim in Year 2 (waiting to obtain data).
Specific Aim 5: Maintain the CLIC website http://clic.berkeley.edu Exit to facilitate communication among CLIC members and outside communities.
The CLIC website has been upgraded from a collection of static html pages to a dynamic site, which can be updated by approved users. A “member’s only” section has been created, accessible via a user authentication process, which includes announcements of activities, events and forums, and a document posting and tracking system. Dedicated sections for CLIC Interest Groups, Logistic Groups, and Working Groups have been added where group members can post messages and documents to facilitate communication and exchange of ideas. Approved members have viewing, editing or administrative rights within these groups. These features of the CLIC website currently are being tested and will be opened for CLIC member use [members will be invited to obtain user names] by June 2011. Other features currently are in development.
Significance
Leukemia is the most common type of childhood cancer. About 2,400 cases of childhood leukemia (ages 0-14 years) are diagnosed annually in the United States. The etiology of childhood leukemia is complex; confirmed clinical and epidemiologic associations explain less than 10% of childhood leukemia incidence. Project 1 is the first epidemiologic study to date that proposes to collaborate with a large international group of investigators in order to examine ubiquitous environmental exposures (i.e., tobacco smoking and residential pesticides) that may be causally associated with the most frequent cancer in children. Pooling data from 14 case-control studies presents a unique opportunity to fully investigate the critical periods of exposures to these contaminants and the possible modifying effects of metabolizing genes in the etiology of childhood, and to examine rare and less-studied childhood leukemia types like acute myeloid leukemia and other cytogenetic subgroups.
RD834511C002: Exposure Assessment for Childhood Leukemia
Specific Aim 1: Measure cotinine, polychlorinated biphenyls (PCBs), and polybrominated diphenylethers (PBDEs) in serum samples obtained from 250 childhood leukemia cases at diagnosis. Estimate correlations in analyte levels between serum and house dust samples.
No activities were conducted on this aim in Year 2.
Specific Aim 2: Investigate effects of time and seasonality on house dust levels of PBDEs.
- Measure levels of PBDEs in the 500 household-dust samples (original and repeat dust samples from each of 250 households. Repeat dust sampling and measurements of nicotine, PAHs and, PCBs will be conducted under NIEHS grant 1R01-ES015899-01A2).
- Use mixed-effects models of levels of PBDEs in house dust to evaluate trends, seasonality, and within-household variability.
During Year 2 we made progress on Aims 2a and 2b. Repeat dust samples have been collected in 204 households (a total of 408 original and repeat samples available for proposed analyses). Using the analytical method developed in Year 1, we extracted PBDEs from 357 residential-dust samples and purified the extracts with silica gel and gel permeation chromatography in preparation for mass spectrometry. We have thus far measured 22 PBDE congeners in 143 (out of a total of 357) residential-dust samples via gas chromatography-high resolution mass spectrometry. We also developed mixed models for statistical analysis of PBDE levels in house dust and applied them to a training set obtained from another investigation of residential dust in Fresno, California.
Specific Aim 3: Develop and apply methods for detecting and profiling human serum albumin (HAS) adducts in samples of dried blood spots (DBS) and serum.
- Develop methods for measuring HSA adducts in DBS.
- Measure profiles of HSA adducts in DBS from leukemia cases and matched controls. Compare profiles between childhood leukemia cases and controls.
- Measure profiles of HSA adducts in serum from leukemia cases at diagnosis. Compare profiles of HSA adducts from leukemia cases measured in DBS and serum.
Specific Aim 4: Identify HSA adducts observed in profiles, paying particular attention to adducts associated with leukemia status and changes from birth to diagnosis.
Specific Aim 5: Develop and apply quantitative assays for HSA adducts identified in Aim 4.
- Develop assays for isotope-dilution mass spectrometry of identified adducts.
- Investigate the stability of these adducts in DBS from control children of smoking and nonsmoking mothers.
- Quantify levels of these adducts in archived profiling samples from Aim 3 and investigate possible associations with self-reported parental smoking and house dust levels of nicotine, polycyclic aromatic hydrocarbons (PAHs), PCBs, and PBDEs.
During Year 2, we made progress on Aims 3a, 4, and 5a. With the goal of optimizing the DBS sample preparation prior to profiling HSA adducts, we developed a pressure-cycling method that combined DBS protein extraction and trypsin digestion in one step lasting only 30 minutes. This resulted in comparable results to those obtained with our conventional method applied to HSA from serum, which requires overnight protein extraction followed by 6 hours of trypsin digestion. After extraction and digestion of 3-mm punches from DBS, samples were purified by off-line high-performance liquid chromatography (HPLC) and the (T3) fraction containing HSA-Cys34 adducts was collected using a reverse phase C8 column. The gradient was chosen to minimize the volume of the collected fraction and thereby to maximize the concentrations of adducts in the sample. Then, liquid chromatography-selected reaction monitoring (LC-SRM) experiments were performed on the HPLC samples to detect T3-quinone adducts of selected quinones that were anticipated to be present in DBS samples. By comparing the selected reaction monitoring (SRM) extracted ion chromatograms from DBS digests with those of synthetic T3-quinone standards, the following putative identifications were assigned to analytes in the DBS samples: diol and oxidized forms of benzoquinone, naphthoquinone and phenanthrene quinone.
Significance
Leukemia is the most common type of childhood cancer. About 2,400 cases of childhood leukemia (ages 0-14 years) are diagnosed annually in the United States. The etiology of childhood leukemia is complex; confirmed clinical and epidemiologic associations explain less than 10% of childhood leukemia incidence. The results of this study are providing extremely important information regarding the contribution of various environmental, infectious, immune, and genetic factors to the risk of childhood leukemia. This Center proposes to conduct multi- and inter-disciplinary research to examine the interplay of environmental, genetic and epigenetic factors of childhood leukemia, with a focus on children’s exposure to common chemicals with strong biologic plausibility, i.e., benzene, cotinine, PAHs, PCBs, and PBDEs. Work in year 2 tentatively identified several quinone adducts of benzene and PAHs (benzoquinone, naphthoquinone, and phenanthrene quinone) in DBS.
PBDEs are the most common brominated flame retardants in the United States; they are persistent and ubiquitous environmental contaminants. The U.S. National Toxicology Program showed that high doses of one PBDE mixture were carcinogenic in rodents. Human studies have found a suggestive relationship between another PBDE mixture in adipose tissue and the risk of non-Hodgkin’s lymphoma. Contact with house dust is thought to account for 80-90% of the total PBDE exposure, in large part because PBDEs originate entirely from indoor consumer products. California residents may be at particular risk to the effects of PBDEs due to the State’s flammability standards that motivated increased use of PBDEs in furniture sold in California. This project will improve chemical exposure assessment using direct measures of chemicals in home dust samples and biomarkers.
RD834511C003: Prenatal Exposures, DNA Methylation, & Childhood Leukemia
Specific Aim 1: Characterize the DNA methylation pattern of normal B-cell differentiation as compared to their leukemic cell counterparts.
We have continued our research activities on characterizing the normal pattern of DNA methylation during B-cell differentiation. This activity is dependent upon two key activities: obtaining high quality primary normal bone marrow, and high quality cell sorting procedures for fine sorting of pre-B cell populations. In our progress report from last year, we identified sources for the normal B-cell populations and have performed pilot experiments to sort these populations. Bone marrow is obtained from fetal sources, from children who have recovered from leukemia (who are relatively age-matched to our population of interest), and young adults. We are therefore able to assess DNA methylation patterns in ontological stages and calendar ages. An example of our cell sorting was demonstrated in Figure 1 from last year’s progress report, and a number of genes that were identified as being de-methylated and methylated are shown in Figure 1 in this year’s report. The presence of CD19 as one of the loci that lost methylation is a testament to the success of this experiment. This involves the use of the Illumina 27,000 CpG site array, but our larger experiments are currently under way using the Illumina 486,000 CpG site array, which will provide much more detailed and extensive data than we originally proposed.
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Figure 1: Top genes increased and decreased in DNA methylation status during the B-cell progenitor differentiation. The list of genes with increased and decreased methylation during differentiation of stem cells to pre-B cells. Cells from two fetuses at 22 weeks were sorted into CD34++; CD34+, CD19+; CD34-, CD19+, CyIgM-; and CD34-, CD19+, CyIgM+ cells. DNA was run on the Illumina 27,000 CpG site infinium array. After filtering for loci that were not concordant between the two subjects, the beta values were averaged and those with the largest increases and decreases are shown in the figure. |
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We now have carefully assessed and chosen 253 case and 260 control samples with the most extensive data available regarding smoking, pesticides, and other exposure information with which to complete the aims of this proposal. These DNAs and their matched Guthrie cards will be analyzed during 2011 using Year 2 funds and Year 1 carry-forward funds. This DNA will be bisulfite-treated and processed by the UCSF Center for Human Genetics Core using the 486,000 CpG site array and analyzed in the mid to latter half of this year.
Specific Aim 2: Characterize DNA methylation pattern in 250 neonatal DBS cards from leukemia cases (derived from the same case samples as Aim 1) and 250 controls.
The laboratory component of this aim is currently under way.
Specific Aim 3: Replicate and extend the findings of Aim 1 by characterizing DNA methylation in a set of disease- and exposure-relevant meta-stable CpG sites in DBS cards from select groups of DBS cards from California leukemia cases and controls.
No activities scheduled in Years 2 and 3. We have, however, completed and approved IRB protocols for this work at UC Berkeley and UCSF. We currently are submitting our IRB for approval at the State of California level.
Core A: Administrative Core
Specific Aim 1: Assist the Center Director in the daily planning, execution, and coordination of the Center.
Specific Aim 1 is proceeding according to schedule. Members of the Internal Advisory Committee including the Project and Core Directors, Pediatric Health Specialists, and the Junior Faculty Investigator are meeting monthly to discuss the progress of all three Projects and Cores, as well as any additional needs for administrative support. Decision and action items are summarized in detailed minutes. CIRCLE investigators participate in monthly NIEHS/EPA conference calls with investigators from other Centers.
The IAC has suggested individuals be invited to join the External Advisory Committee (EAC) in order to have expertise in all the Center’s relevant areas of research and outreach. The following candidates are being considered to join the EAC: Andrea Hricko (USC/UCLA), Kathleen Stewart (Region 9 EPA), David Martin (Children’s Hospital Oakland Research Institute), Terry Dwyer (Murdoch Children’s Research Institute), Rob McConnell (USC), Frederica P. Perera (Columbia University), Lauren Zeise (Cal EPA), and Jorn Olsen (Danish National Birth Cohort).
Planning for development of the Center website is under way, in conjunction with leaders of CORE B and Project 1 (Childhood Leukemia International Consortium). In the interim period before the Center website is operational, a secured UC Berkeley portal (Bspace) is being used to post information and facilitate communication among Center members.
A Quality Assurance Plan was written and approved by EPA.
Specific Aim 2: Provide scientific leadership for the overall Center.
The Center Director (Patricia Buffler) and co-Director (Catherine Metayer) represented CIRCLE at the 2010 Children’s Center Meeting in Boston (October 18) and presented an overview of the Center. The leader of the Research Translation and Community Outreach Core B (Amy Kyle) and one of the Pediatric Health Specialists (Mark Miller) also attended, including the joint meeting with the Pediatric Environmental Health Specialty Unit (PEHSUs).
Stephen Rappaport (Project 2 leader) gave the keynote address to an audience of 170 scientists from the NIH Genes, Environment, and Health Initiative (GEI) Exposure Biology Program in April at the fourth annual NIEHS grantee meeting. His presentation addressed using the “exposome” – the collective of lifetime exposures from all sources including air, water, occupation, behavior, stress, food and internal sources (e.g., metabolites produced by inflammation, oxidative stress, and gut flora) when studying environmental health. He proposed that an examination of the “exposome” will result in more quantitative methods for measuring exposures as opposed to qualitative self-reporting.
Following a series of discussions at Internal Advisory Committee meetings, the Pediatric Health Specialists, Drs. Mark Miller and Gary Dahl developed a survey to assess attitudes and practice regarding addressing environmental exposures among pediatric oncologists. They also organized lectures at Stanford University School of Medicine to increase awareness within the medical community about environmental epidemiology and childhood cancer. CIRCLE investigators were invited to present leukemia research related to CIRCLE (e.g., methylation studies, impact of smoking on the risk of childhood leukemia). The long-term goal of this initiative is to encourage pediatric oncologists to incorporate environmental history in the patient assessment at diagnosis and provide instruction on how to take an environmental history.
Recruitment for the junior faculty investigator position was completed, and Dr. Libby Morimoto was hired as the new junior faculty level investigator in August 2010. Dr. Morimoto has a Ph.D. in Epidemiology and 2+ years of post-doctoral research in genetic and molecular epidemiology. She has significant research experience and several peer-reviewed publications in the molecular and environmental epidemiology of cancer. The Junior Faculty Investigator, Dr. Morimoto has taken an active role in CLIC (Project 1). This consortium is organized in groups to promote collaborative research in specific areas and to facilitate CLIC-wide logistic support. Dr. Morimoto coordinates and facilitates communication within and between these groups. She also participates in the CLIC Management Group that is responsible for the overall coordination of CLIC. She has written grants to support the development of a centralized data repository [AACR/submitted 12-15-2010] and to provide additional funding for the 2011 CLIC annual meeting in Barcelona [NIEHS/submitted 4-12-2011]. Under the mentorship of Drs. Buffler and Metayer, she is involved in the scientific direction of several CLIC pooled analyses proposed in Project 1 and in CLIC-wide genome-wide association studies of ALL.
Part of the commitment of the Center in supporting the career development of Dr. Morimoto is to provide opportunities to develop independent research projects and secure independent funding under the guidance of her mentoring committee [Dr. Patricia Buffler, Dr. Catherine Metayer, Dr. Steve Rappaport, Dr. Joseph Wiemels, Dr. Lisa Barcellos, and Dr. Steve Selvin]. To this end, Dr. Morimoto is developing a pilot study to assess the feasibility of conducting a case-control study of childhood leukemia in Guatemala, in collaboration with Drs. Dahl and Luna-Fineman at the Stanford University School of Medicine. The large population of indigenous and mixed (mestizo) ethnic groups in Guatemala would provide the opportunity to determine how racial differences in leukemia incidence might be related to environmental exposures. This pilot study, if funded, also will provide the preliminary data to support a larger case-control study to elucidate the etiology of leukemia, especially acute myeloid leukemia, by exploring the role of environmental exposures (in particular high indoor exposure to biomass fuel) and the influence of genetic and epigenetic factors. This independent research project may serve as a stepping stone for Dr. Morimoto to apply for, and receive, an independent R01 by the end of the Center grant cycle.
In addition, Dr. Morimoto is examining the validity of using maternal biospecimens to estimate early childhood environmental exposures using data from the California Childhood Leukemia Study. Preliminary results from this analysis suggest that maternal serum cotinine may provide a useful complement to self-reports and environmental sampling in the estimation of childhood exposure to tobacco smoke, particularly among children of non-smoking mothers (abstract submitted to the 2011 International Society for Environmental Epidemiology Annual Meeting). This work will inform some of the biomarker studies proposed in Project 2.
Core A also coordinated efforts to present several abstracts at the annual ISEE meeting in Barcelona.
Specific Aim 3: Provide and maintain access to research data and specimens.
Material Transfer Agreements are in place to provide data and specimens from the California Childhood Leukemia Study (CCLS) to CIRCLE research projects. We completed the selection of CCLS subjects with bone marrow specimens (250 cases) and archived newborn blood specimens (250 cases and 250 controls) that will be used for the methylation studies in Project 3. Transfer of bio-specimens is under way. Core A also assists investigators in preparing IRB applications, including applications to the State of California Genetic Disease Branch for the use of neonatal blood spots for Project 3.
Significance
Leukemia is the most common type of childhood cancer. About 2,400 cases of childhood leukemia (ages 0-14 years) are diagnosed annually in the United States. The etiology of childhood leukemia is complex; confirmed clinical and epidemiologic associations explain less than 10% of childhood leukemia incidence. The results of this study are providing extremely important information regarding the contribution of various environmental, and genetic factors to the risk of childhood leukemia.
Future Activities:
RD834511C001: Childhood Leukemia International Consortium Studies
Specific Aim 1: Continue data pooling. Complete inventory of cytogenetic data. Continue development of meta-database. Organize the 2011 CLIC meeting in Barcelona (September 16-18) in conjunction with the conferences of the International Society for Environmental Epidemiology (ISEE) and the International Childhood Cancer Cohort Consortium (I4C).
Specific Aim 2: Start statistical analyses.
Specific Aim 3: Start statistical analyses.
Specific Aim 4: Assess availability of genetic data for pooled analyses.
Specific Aim 5: Continue website maintenance. Incorporate meta-dabase to allow web-based inventory of questionnaire and biospecimen data.
RD834511C002: Exposure Assessment for Childhood Leukemia
Specific Aim 1: Adapt and validate methods to measure cotinine, PCBs, and PBDEs in serum samples. Identify samples from 250 childhood leukemia subjects for analysis.
Specific Aim 2: Continue to analyze PBDEs in archived and repeated dust samples.
Specific Aim 3: Optimize methods for profiling HSA adducts from DBS samples. Profile HSA adducts in 3-mm punches from DBS from control children divided equally between smoking and non-smoking mothers during pregnancy.
Specific Aim 4: Continue with identification of adducts detected in DBS samples.
Specific Aim 5: Continue with quantification of putative adducts in DBS samples from control children of smoking and nonsmoking mothers.
RD834511C003: Prenatal Exposures, DNA Methylation, & Childhood Leukemia
Specific Aim 1: We will complete the isolation of DNA and perform Illumina Infinium DNA methylation screens on 250 diagnostic bone marrow mononuclear cell preparations. We will complete the same Infinium panel on several stages of B-cell precursor populations among eight fetal B-cell preparations, to establish the DNA methylation pattern of B cell development. In addition, we will perform gene expression arrays on the fetal bone marrows to detect which gene methylation changes are associated with functional changes in expression.
Specific Aim 2: We will complete the processing of 250 case and 250 matched control Guthrie cards for DNA methylation assessments by the Illumina Infinium method.
Specific Aim 3: We will commence the collection of Guthrie cards for this Aim by completing the IRB process first. Biological assays will be performed in future years.
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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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) R834511 (Final) |
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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) R834511 (Final) |
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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) R836159 (2018) R836159 (2019) R836159C003 (2016) |
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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) R834511 (Final) |
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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) R834511 (Final) |
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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) R834511 (2014) R834511 (Final) |
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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) R834511 (Final) |
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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) R834511 (Final) |
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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) R834511 (Final) |
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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) R834511 (Final) |
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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 (13 pp.). |
R834511 (2013) R834511 (Final) |
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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) R834511 (Final) |
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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) R834511 (Final) |
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Progress and Final Reports:
Original Abstract 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
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2014 Progress Report
- 2013 Progress Report
- 2012 Progress Report
- 2011 Progress Report
- Original Abstract
13 journal articles for this center