2014 Progress Report: 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 Period Covered by this Report: September 25, 2013 through September 24,2014
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 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 Center, referred to as Center for Interdisciplinary Research on Childhood Leukemia and the Environment (CIRCLE) includes three Research Projects and two Cores.
R834511C001: 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.
R834511C002:  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.
R834511C003: 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.
CORE A: Administrative Core
Core A will provide: (1) oversight, coordination, and integration of Center activities; (2) scientific leadership; and (3) centralized data management support.  Core A will establish and manage Internal and External Advisory Committees; appoint and collaborate with two Pediatric Health Specialists, and support the research career development of new, junior faculty-level investigators within the structure of the Center.
CORE B: Research Translation and Outreach Core
Core B, the Research Translation and Community Outreach Core (RTCO Core), will disseminate findings from each project to various audiences with common interest in the etiology of childhood leukemia.  Community engagement will be coordinated through the RTCO Core, with the assistance of the Pediatric Health Specialists.

Progress Summary:

R834511C001: Childhood Leukemia International Consortium Studies 
Specific Aim 1:  Pool data elements collected from 14 CLIC case-control studies in 10 countries.
General update: More than 40 participants attended the 2013 CLIC Annual Meeting held in Montreal on September 3-4.  The CLIC investigators leading pooled analyses presented updates and preliminary results during special workshops to enhance scientific interaction between investigators of participating studies. There was interest in addressing methodological issues to evaluate the impact of selection and misclassification biases in CLIC pooled analyses. A new childhood leukemia study from Denmark applied for CLIC membership and was granted Associate study level, and will be eligible to become an Active study once it contributes to pooled analyses. Also, CLIC members discussed the expansion of CLIC to other childhood cancers, leveraging CLIC infrastructure.
The CLIC Management Group (chaired by Prof. Metayer, Director of CIRCLE) continues to hold regular conference calls to discuss issues related to data pooling, progress on proposed pooled analyses, CLIC guidelines, and organization of the CLIC annual meeting. The Data Coordinating Center hosted by the Section of Environment and Radiation at IARC in Lyon, France, under the direct supervision of the Section Head, Dr. Joachim Schüz (CLIC Member) now is in place to (a) collect individual and pooled available CLIC data for centralized storage under a data transfer agreement, (b) prepare datasets by harmonizing across study centers, (c) maintain records of study specific knowledge important for future pooled analyses, and (d) distribute data to CLIC Principal Investigators for future projects. The Data Coordinating Center received data from several studies and will continue to work with the other studies willing to transfer data . Transfer and harmonization of interview and genetic data needed for the proposed pooled analyses are complete. 
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.
Drs. Zhang and Metayer completed an extensive literature review on the worldwide incidence of acute promyelocytic leukemia, a rare type of acute myeloid leukemia, published in Blood Reviews (2014). The review for completeness and accuracy of cytogenetic data in CLIC studies was completed, and risk analyses were conducted by cytogenetic subtype as described below when sample sizes were appropriate.
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.
The analyses for childhood ALL (n~9,000) showed no associations with maternal smoking before and during pregnancy, but increased risks of small magnitude were observed with paternal smoking before conception and during pregnancy. Data also suggested that both maternal and paternal smoking after birth slightly increased the risk of childhood ALL with risk increasing with larger number of cigarettes smoked per day. Additional methodological evaluations of selection and misclassification biases are under way. The analyses for childhood AML (n~1,500) led to similar findings as ALL. Elevated risk were seen for ALL with high-hyperdiploidy and t(12;21) translocation. For AML, the highest risk was seen for myelomonocytic type, a subtype common in treatment-related AML. Results were presented at the International Epidemiology Association, World Congress of Epidemiology, and two manuscripts are under review by the CLIC co-authors. The analyses for home pesticide use before and/or after birth were completed and showed a 1.4-fold increased risk of childhood ALL overall; elevated risks were observed for most subtypes and with most types of pesticides. An elevated risk of AML was reported for pre-natal exposure only (manuscript was submitted to the International Journal of Cancer). Additional analyses on parental occupational exposure to pesticides were performed. Based on ~8,240 ALL cases, and 14,850 controls from 11 studies, the odds ratio (OR) for paternal preconception exposure to pesticides at work was 1.20 [95% confidence interval (CI): 1.06-1.38], whereas no association was seen with maternal occupational exposure during pregnancy. In contrast for AML, the OR for maternal exposure during pregnancy was 1.94 (95% CI: 1.19-3.18) based on ~1,330 cases and 12,140 controls; no association was seen for preconception paternal exposure (published in the International Journal of Cancer).
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.
Analyses for gene-environment (GxE) interaction remained limited in scope as only four studies have comparable genetic and environmental data. GxE analyses for childhood ALL are under way for parental smoking and genes NQ01, NAT2, CYP1A1, and GST, and for home use of pesticides and genes CYP1A1, NAT2, and PON1. CLIC studies also participated in the validation of newly developed methods to conduct GxE analyses with genome-wide data (manuscript in preparation).
Specific Aim 5:  Maintain the CLIC website http://clic.berkeley.edu to facilitate communication among CLIC members and outside communities.
The CLIC website is being maintained and updated and used regularly by CLIC collaborators.
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 that proposes to collaborate with a large international group of investigators 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.
R834511C002: 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.
In Year 5, multivariable linear regression models were used to evaluate the relationship between natural-log transformed blood-POP concentrations and natural-log transformed dust-POP concentrations, with the following explanatory factors considered for inclusion in each model: the child's age, sex, ethnicity, and breastfeeding duration; the mother’s age and country of origin; the household’s annual income; and the blood sampling date. Blood concentrations of PCBs 138 and 153 were positively associated with the child’s breastfeeding duration, household annual income, and PCB-dust concentrations (+110% and +94% per 2.7-fold increase in PCB-dust concentrations, respectively). Likewise, BDE-153-blood concentrations were positively associated with the corresponding dust concentrations (+44% per 2.7-fold increase in dust concentrations). In contrast, we did not observe a significant relationship between blood concentrations and dust concentrations of two other major POPs, p-p’-dichlorodiphenyldichloroethylene (p-p’-DDE) and BDE-47.  A manuscript describing our findings is being revised prior to submission for publication in a peer-reviewed scientific journal.
Specific Aim 2: Investigate effects of time and seasonality on house dust levels of PBDEs.
a)   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).
b)   Use mixed-effects models of levels of PBDEs in house dust to evaluate trends, seasonality, and within-household variability.
In Year 5, we used mixed-effects models of house-dust PCB concentrations to estimate variance components and identify sources of variability.  We observed decreasing trends in PCB concentrations in house dust over time.  Although house dust concentrations at baseline (2001-2007) were significantly correlated with concentrations from repeat samples (2010) for each PCB, substantial within-household variability was observed.  Indeed, the variability in concentrations within a household (over time) was generally similar in magnitude to the variability between households (across the population).  We were able to identify several factors that explained some of the variability between households, including the age and size of the home. We were able to identify several factors that influenced the indoor residence times of PCBs, including floor replacement between visits.  A manuscript describing the mixed-effects modeling of house-dust PCB concentrations has been published in Environmental Science & Technology.
Specific Aim 3:  Develop and apply methods for detecting and profiling human serum albumin (HSA) adducts in samples of dried blood spots (DBS) and serum.
a)   Develop methods for measuring HSA adducts in DBS.
b)   Measure profiles of HSA adducts in DBS from leukemia cases and matched controls.  Compare profiles between childhood leukemia cases and controls.
c)   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.
During Year 4, we reported an untargeted method for profiling HSA adducts at the Cys34 locus in proteins extracted from DBS. Although we were able to successfully adapt this method to perform a pilot study with 46 DBS from control children (50% from smoking mothers and 50% from nonsmoking mothers), the assay included many cumbersome steps that led to marginal precision with CVs typically being greater than 50% for individual adduct bins. Given this level of imprecision and the small number of DBS, it was, perhaps, not surprising that none of the 67 adducts detected in fetal ANBS were associated with maternal smoking. Furthermore, triple-quadrupole MS used for this assay could not differentiate among multiple adducts in a given mass bin and did not provide accurate masses for annotation of adduct features that would be needed for identification.  
In Year 5, we restructured the DBS assay to simplify processing and employed nanoflow liquid-chromatography high-resolution mass spectrometry (LC-HRMS) to obtain accurate masses of individual adduct features. These modifications took advantage of parallel development of methods for performing Cys34 adductomics with serum samples that was supported by other funding sources. The number of assay steps was reduced from seven to three and time consuming buffer exchanges were eliminated. Importantly, by using centrifugal filtration to separate proteins from small molecules, we were able to perform small-molecule omics (‘metabolomics’) with the same 3-mm punch. We then applied the updated assay to the same 46 DNBS from infants of smoking and nonsmoking mothers and confirmed the presence of 33 Cys34 adducts in these specimens. 
Specific Aim 4:    Identify HSA adducts observed in profiles, paying particular attention to adducts associated with leukemia status and changes from birth to diagnosis.
Several putative adducts were annotated, including a number of Cys34 oxidation products and rearrangements, a host of mixed disulfides, and modifications by formaldehyde and acrolein. None of these adducts had ever been reported in neonatal DBS. Levels of 2 of the 18 adducts differed significantly between infants of smoking and nonsmoking mothers. The assay also generated profiles of 4,500 small molecules, 500 of which were annotated via accurate masses and MS/MS in metabolomics databases.  These successful modifications and enhancements to omics analyses of DBS motivated our renewal proposal for Project 2.
Specific Aim 5:    Develop and apply quantitative assays for HSA adducts identified in Aim 4.
a) Develop assays for isotope-dilution mass spectrometry of identified adducts.
b) Investigate the stability of these adducts in DBS from control children of smoking and nonsmoking mothers. 
c) 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.
       This aim was not pursued during Year 5.
Significance
Although leukemia is the most common type of childhood cancer, the etiology of childhood leukemia is complex and confirmed clinical and epidemiologic associations explain less than 10% of childhood leukemia incidence. The results of this study are providing important information regarding the contribution of various environmental, infectious, immune, and genetic factors to the risk of childhood leukemia. This Center is conducting research to examine the interplay of environmental, genetic and epigenetic factors of childhood leukemia, with a focus on children's exposures to common chemicals with strong biologic plausibility, i.e., benzene, nicotine, PAHs, PCBs, and PBDEs. In particular, PBDEs are the most common brominated flame retardants in the United States; they are persistent and ubiquitous environmental contaminants that have been implicated with cancer in humans and animals. 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. Work in Project 2 is quantifying PBDEs in both house dust and serum from childhood leukemia cases. 
Preliminary work in Project 2 has shown that profiles of HSA adducts and scores of small molecules can be measured in 3-mm punch samples from neotatal DBS of control children. Because HSA persists in human blood for a month, such measurements of adducts in fetal DBS will provide valuable information about fetal exposures during the final month of gestation.
R834511C003: Prenatal Exposures, DNA Methylation & Childhood Leukemia
Aim 1: Characterize the DNA methylation pattern of normal B-cell differentiation as compared to their leukemic cell counterparts.
 
Our first aim was to characterize the DNA methyation patterns of normal pre-B cells, and those that distinguish pre-B cells from leukemia cells.  This aim would help to identify those DNA methylation changes that are critical for leukemogenesis. Examination of the pre-B cell methylation pattern discovered a demethylation signature during B-cell development, and a transcription factor network that involved sequentially demethylated pre-B cell transcription factors, which we published in a previous grant period (Lee et al., 2012).  In the grant period covered by this report (2013-14) we also have characterized the leukemia methylome in relation to pre-B cells, and found that leukemias co-opt a mechanism encoded by the polycomb modifiers to induce DNA methylation changes (Lee et al., 2015); these modifiers are generally active only in early embryo stem cell development. We found that about 10% of the assessed CpG sites were changed in DNA methylation status in leukemia (Lee et al., 2015).  These changes provide us with a template for evaluating the biological significance of the changes that we detect from environmental inputs in Aims 2 and 3. Along with construction of this template, we have discovered other significant tumor genetic-epigenetic cooperation in leukemogenesis – one of these is the tight functional association between RAS mutation and epigenetic modification of the PTPRG gene, which we have recently reported (Xiao et al., 2014).
 
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.
In our second aim, we sought to characterize DNA methylation pattern in 250 neonatal DBS cards from leukemia cases (derived from the same case samples as Aim 1) and 250 controls. Upon our initial experiments examining DNA methylation in perinatal bloods (neonatal blood spots), we discovered that much of the variation in DNA methylation was connected to normal variances in the proportions of various blood cell types (B- and T-cells, neutrophils, etc.). Such variation complicates the investigation of environmental chemical stressors and DNA methylation at specific CpG sites. However, significant improvements to analytical procedures for removing bias or confounding by differences in cell distribution have been developed by our extended research team, which includes DNA methylation experts John Wiencke, Karl Kelsey, and Andy Houseman. We recruited Andy Houseman, the leading statistician for developing methodology relating to this concept, to our research team. Every blood cell type has its own distinct DNA methylation pattern, and environmental factors, genetics, and infections or other factors may influence the growth patterns of various blood cell types. Taking into account these cell distribution differences in DNA methylation, the precision of our environmental exposure-DNA methylation comparisons have increased. In Figure 1 we show such an analysis incorporating a cell reference-adjusted analysis of polycyclic aromatic hydrocarbon exposure measured in Project 2 (Deziel et al., 2014) on CpG methylation in neonatal blood spots. The CpGs derived from this result, replicated in two different sets of blood spots from children who contracted leukemia later in life, included a number of markers that are altered in leukemia cells thus forming a basis for mechanism of action by which PAH may increase the risk of leukemia. Additional such analyses were performed for self-reported smoking, house-dust measured PCBs (Ward et al., 2009), DDT and DDE, and self-reported exposures to pesticides. These analyses have resulted in the determination of a panel of replicated CpG sites using the Illumina HM450K platform, which also are implicated in leukemogenesis. Manuscripts detailing these results and further replication of CpG sites are in preparation.
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.
In our third aim, we sought to replicate and extend the findings of Aim 1 by characterizing DNA methylation in a set of disease- and exposure-relevant metastable CpG sites in DBS cards from select groups of DBS cards from California leukemia cases and controls. This additional validation of the CpG sites that change DNA methylation status currently are taking place, with CpG sites chosen for validation derived from those that are significant with environmental risk factors, in regulatory regions of genes such as gene promoters, and are altered in leukemias (based on Aim 1 results). We also have recently sought funds as a supplement to produce more HM450K data on a new set of CCLS cases and controls in order to perform much more extensive replicaiton and meta-analyses.
Significance
The etiology of childhood leukemia is complex; confirmed clinical and epidemiologic associations explain less than 10% of childhood leukemia incidence. Despite the recognition that certain genotoxic exposures such as diagnostic radiation during pregnancy cause leukemia in children, leukemia rates have not fallen; rather, there is an increased incidence over the past 50 years. Part of this increase in incidence is likely due to changes in patterns of exposure to manufactured and natural chemicals introduced into a child’s environment, and also changing patterns of infectious disease exposure and severity. 
DNA methylation is a process of marking genes during development for the compression of chromatin and an “off” signal for expression. DNA methylation also is vital for suppressing recombinogenic regions of the genome such as retrotransposon fossils. Environmental exposures may impact the signal transduction pathways that lead to DNA methylation, and/or affect DNA methylation directly, causing aberrant DNA methylation patterns and changes in the methylation status of individual critical genes. Project 3 studies the association of precisely assessed chemical measurements in California Childhood Leukemia Study participant’s birth bloods in cases and controls with DNA methylation status in the same birth bloods as well as leukemic bone marrows (among cases only).  Our comprehensive examination and integrated statistical analysis will reveal new relationships and pathways between environmental exposures and key epigenetic factors that impact the genesis of acute lymphocytic leukemia in children.
CORE A: Administrative Core
Aim 1:  Assist the Center Director in the daily planning, execution, and coordination of the Center.
The administrative staff continues to provide support for all activities for all components of the Center.
Aim 2:  Provide scientific leadership for the overall Center.
Catherine Metayer, MD, PhD (Associate Adjunct at the School of Public Health, UC Berkeley) became the Director of CIRCLE after Patricia Buffler’s sudden passing, and successfully ensured the continuity of all research and administrative activities related to the Center. Core A oversaw a series of meetings of the Internal Advisory Committee to determine the focus, goals, and the direction of the Center for the next budget cycle. Core A then oversaw preparation of the continuing renewal application. Core A also coordinated the participation of the Center members in the EPA/NIEHS webinars and Center working groups. Core A continued to provide leadership in the fostering of young Investigators. Several graduate students and post-doctoral fellows from UCB and UCSF regularly attend the Research Coordination meetings led by Dr. Metayer, providing opportunities to discuss ongoing and future studies that include not only research within CIRCLE but also from other childhood leukemia and cancer studies in our group. Senior researchers on campus (i.e., Dr. Barcellos) and from other institutions (i.e., Dr. Ma at Yale, Dr. Ward at the National Cancer Institute) also participated in these meetings. Dr. Francis, a post-doctoral fellow with interest in viral discovery studies of childhood leukemia, also attended the Internal Advisory Committee meetings, resulting in the establishment of a collaboration with Dr. Dahl (see below) and Dr. Rappaport to design a pilot case-control study of childhood leukemia at Stanford University to obtain adequate biospecimens for metabolomics and other “omics” studies, and with Dr. Kogan at UCSF to validate findings in mouse models.
 
Pediatric Health Specialists (PHS)
Drs. Dahl and Miller (PHSs) conducted a survey of nearly 200 pediatric oncology clinicians indicating that the clinicians feel ill-prepared to answer questions about the role of environmental factors in childhood illness (manuscript submitted). Drs. Dahl and Metayer collaborated with Dr. Miller to write a commentary for the Environmental Health Policy Institute of Physicians for Social Responsibility. Dr. Miller presented CIRCLE research findings to clinicians at the Pediatric Academic Societies (PAS) annual meeting (2014) and chaired the first ever session devoted to childhood cancers at the 2014 conference of the International Society for Environmental Epidemiology. He developed a session for the PAS annual meeting in 2015 (Childhood Leukemia: A Preventable Disease?) that was accepted. Dr. Miller, with support from Dr. Dahl and CIRCLE investigators developed an interactive e-book chapter on leukemia and the environment (http://coeh.berkeley.edu/ucpehsu/) that highlights CIRCLE research; the e-book will be available for continuing education credits through the Centers for Disease Control and Prevention. The PHSs also collaborated with CIRCLE investigators to present a seminar series at Stanford University translating CIRCLE research findings to clinical practice and training. Dr. Miller collaborated with the California Cancer Registry to conduct descriptive analyses of trends in childhood leukemia incidence demographic characteristics (manuscript in preparation). The PHSs also contributed to Core B educational materials for non-researchers.
Dr. Gary Dahl, continues to collaborate with Center members Dr. Steve Rappaport, Steve Francis (graduate student), and Erin Breese, a Fellow at Stanford, on a genomics/metabolomics pilot study that grew out of discussions during Center IAC meetings.  The aims of the pilot will be to compare protein adducts on the serum albumin between cases and controls and to compare identifiable and non-identifiable nucleic acids processed from total RNA between leukemia patients and controls (enrollment started in 2014)
 
Junior Faculty Development
Dr. Morimoto, the Center’s Career Development Investigator, submitted an R01 application to the NIEHS, to fund a fully powered study to assess the effects of exposure to wood smoke and Native American ancestry on leukemia risk and received a score of 31 (18th percentile). Dr. Morimoto became a CLIC member, and is exploring collaborations with other CLIC studies of Latino children. She expanded her research portfolio to genetic and biomarker studies of childhood leukemia and other cancers, and is Co-Investigator on other projects with CIRCLE Co-Investigators (Drs. Metayer, University of California Berkeley [UCB]; Wiemels, University of California San Francisco [UCSF]; Ma, Yale University). She completed an analysis of birth characteristics and risk of pediatric rhabdomyosarcoma in California (manuscript in preparation). She also has been leading a series of workshops on genetic analyses to update research staff on novel analytic techniques for genome wide association and gene pathway analyses.
Aim 3:  Provide and maintain access to research data and specimens.
CORE A continues to provide Material Transfer Agreements to provide data and specimens from the CCLS to CIRCLE research projects 1, 2 and 3.  Core A also assists investigators in preparing IRB applications. Dr. Metayer aids in selecting cases and controls from the CCLS database and biorepository that Dr. Wiemels uses for the replication sets.  Dr. Metayer also provides Dr. Rappaport (Project 2) with the same set of cases and controls that Project 3 will use in a replication study. 
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.
CORE B: Center for Integrative Research on Childhood Leukemia and the Environment
Specific Aim 1:  Develop a narrative that communicates the key questions, findings, and trajectory of future research to find the causes and cures for leukemia in children, to be used as the basis for the research translation and community outreach program.
CORE B completed and posted videos reflecting the work of CIRCLE on its website. Dr. Kyle remains active in the NIEHS Partnership for Environmental Public Health and has been selected to present a workshop at a multi-agency meeting to be held during the last week of July at RTP.  She also provided a talk at a national webinar organized by the U.S. EPA.
Specific Aim 2:  Engage with two non-governmental organizations that serve parents, health/child care professionals, community leaders, policy leaders, and other advocates interested in children’s environmental health to develop relevant messages and materials about childhood leukemia and opportunities and challenges of research in this field and to convey and distribute this information to key audiences.
Partnerships with the Children’s Environmental Health Network (CEHN) and the Pediatric Environmental Health Specialty Unit (PEHSU) at UCSF continue to be highly successful. 
Specific Aim 3:  Reach out to targeted earned media outlets that report in depth on health, environmental or environmental health topics to generate interest in covering the trajectory of results from research on causes of childhood leukemia, and the promise of future research.
CIRCLE is sponsoring a symposium on “Impacts of Climate Change on Children’s Health” developed during 2014 by the California Environmental Protection Agency (CalEPA), Office of Environmental Health Assessment, along with the UCSF Pediatric Environmental Health Specialty Unit. This is part of our continuing series of children’s health symposia conducted as part of the Children’s Environmental Health Program. The conference is scheduled for March 4 and 5, 2015 at the CalEPA headquarters in Sacramento, CA.
Specific Aim 4: Develop relationships with voluntary organizations, such as the Leukemia and Lymphoma Society, that serve those who have cancer and their families and allies, to increase their awareness of, and possible interest in, research on causes of cancer.  Provide resources of value for one or more of these organizations.
We continued discussions about working with the healthy and smoke free housing communities and organizations to share findings particularly about relationships between smoking and leukemia and also about the contaminants found in dust and their potential health significance for childhood leukemia and potentially other diseases as well. Dr. Miller introduced CIRCLE investigators to Vickie Leonard, RN, FNP, PhDwho is the Program Coordinator for the UCSF PEHSU where she develops educational materials on pediatric environmental health based on current science for both families and clinicians. Drs. Miller and Leornard are developing ideas to incorporate CIRCLE’s findings into these educational materials.
Specific Aim 5:  Develop and convey briefings and updates about advances in knowledge and potential future benefits of research on childhood leukemia to state and national policy and stakeholder audiences, including the California Department of Public Health and the California Environmental Protection Agency, using web-based communication strategies as well as directly targeted communications.
Dr. Kyle remains engaged in briefing government representatives and others about the implications of chemicals policy for children. She also is part of a group advising EPA leaders on actions to implement the Toxic Substances Control Act from a children’s health perspective.
Specific Aim 6:  Work with other children’s environmental health research centers to seek opportunities for combined efforts to enhance outreach and research translation for the program as a whole.
CIRCLE staff Todd Whitehead and Director Catherine Metayer collaborated on a grant proposal with Dr. Asa Bradman from The CHAMACOS Center at UC Berkeley to propose an intervention study to reduce home indoor contamination with PCBs/PBDEs.
No West-coast symposium was organized in Year 5.
Significance
Research translation and outreach can amplify the public benefits of the investment in research by making the results accessible to key audiences that can support both policy and behavioral changes. The health relevance comes from making both immediate results and broader understanding of results achieved through sustained research available to those who can act upon this knowledge for the public good. Our progress illustrates the potential in using a networked model of research translation and outreach to reach a more diverse audience in conjunction with partners.

Future Activities:

R834511C001: Childhood Leukemia International Consortium Studies 
Specific Aim 1:    Completed.
Specific Aim 2:    Completed.
Specific Aim 3:    Completed.
Specific Aim 4:    Continue GxE statistical analyses for ALL. Insufficient data for AML.
Specific Aim 5:    Completed.
 
R834511C002: Exposure Assessment for Childhood Leukemia
Specific Aim 1:    Perform measurements of cotinine in serum samples.
Specific Aim 2:    Completed.
Specific Aim 3:    Profile HSA adducts in 3-mm punches from DBS from 100 childhood leukemia cases and matched controls.
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 childhood leukemia cases and controls.
 
R834511C003: Prenatal Exposures, DNA Methylation & Childhood Leukemia
Specific Aim 1:    We have completed this aim and have published the results (Lee et al., 2012 and Lee et al., 2015).
Specific Aim 2:    We will complete the analysis of 250 case and 250 matched control Guthrie cards for DNA methylation assessments by the Illumina Infinium method, and publish the results on all of our target environmental variables including smoking, pesticides, PCBs, PBDEs, and some nonchemical stressors including dietary quality, birthweight and fetal growth.
Specific Aim 3:    We will complete a replication analysis this year on CCLS case/control cards. Additional cards from the California archive will be analyzed during our no-cost extension period, and we wish to perform more HM450K replication should our supplemental funding request be awarded.
CORE A: Administrative Core
Specific Aim 1:    Continue administrative and research support, and update the CIRCLE website. Pediatric Health Specialists, Drs. Mark Miller and Gary Dahl, will continue to develop short seminar series of environmental and genetic factors in childhood leukemia for clinicians.  Dr. Morimoto will re-submit a R01 after obtaining a score close to the funding range.
Specific Aim 2:    Participate in NIEHS monthly conference calls with investigators from other Centers.
Specific Aim 3:    Continue support for data sharing and database maintenance.
 
CORE B: Center for Integrative Research on Childhood Leukemia and the Environment
Specific Aim 1:    Completed.
Specific Aim 2:    Completed.
Specific Aim 3:    Completed.
Specific Aim 4:    Completed.
Specific Aim 5:    Completed.
Specific Aim 6:    Completed.
 

References:

R834511C003: Prenatal Exposures, DNA Methylation & Childhood Leukemia

Deziel, N. C., Rull, R. P., Colt, J. S., Reynolds, P., Whitehead, T. P., Gunier, R. B., . . . Metayer, C. (2014). Polycyclic aromatic hydrocarbons in residential dust and risk of childhood acute lymphoblastic leukemia. Environ Res, 133, 388-395. doi: 10.1016/j.envres.2014.04.033

Gonseth, S., Roy, R., Houseman, E. A., de Smith, A., Zhou, M., Lee, S. T., . . . Wiemels, J. (2015). Association of estimated periconceptional folate intake on neonatal DNA methylation levels submitted.

Ward, M. H., Colt, J. S., Metayer, C., Gunier, R. B., Lubin, J., Crouse, V., . . . Buffler, P. A. (2009). Residential exposure to polychlorinated biphenyls and organochlorine pesticides and risk of childhood leukemia. Environ Health Perspect, 117(6), 1007-1013. doi: 10.1289/ehp.0900583


Journal Articles: 17 Displayed | Download in RIS Format

Other center views: All 57 publications 17 publications in selected types All 17 journal articles
Type Citation Sub Project Document Sources
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)
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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)
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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 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. R834511 (Final)
    R836159 (2018)
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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. R834511 (Final)
    R836159 (2018)
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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. R834511 (Final)
    R836159 (2018)
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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 (13 pp.). 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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  • Journal Article de Smith AJ, Walsh KM, Francis SS, Zhang C, Hansen HM, Smirnov I, Morimoto L, Whitehead TP, Kang A, Shao X, Barcellos LF, McKean-Cowdin R, Zhang L, Fu C, Wang R, Yu H, Hoh J, Dewan AT, Metayer C, Ma X, Wiemels JL. BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia. Int J Cancer 2018;143(11):2647-2658. R834511 (Final)
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  • Supplemental Keywords:

    Relevant Websites:

    http://circle.berkeley.edu/Center for Integrative Research on Childhood Leukemia Exit

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011 Progress Report
  • 2012 Progress Report
  • 2013 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