Grantee Research Project Results

2012 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 - 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, 2011 through August 24,2012
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 the 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, assisted by 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.

More than 40 participants attended the 2011 CLIC Annual Meeting held in Barcelona (September 16-18) (the meeting minutes are available at http://clic.berkeley.edu). Following up on recommendations from this meeting, a workshop for the Environmental Interest Group was organized by the Leader of Project 1 to discuss sustainable resources for data harmonization across analyses (including those proposed in Project 1), as well as the possibility of conducting geographic information system (GIS) studies within CLIC. The Workshop was sponsored by CHILDREN with CANCER, UK, London (April 27, 2012). Guest speakers from the University of California (Prof. Beate Ritz), the Aarhus University, Denmark (Dr. Thomas Becker), and the International Agency for Research on Cancer (Dr. Ann Olsson) were invited to share their expertise.

The progress reports of the pooled analyses are presented in Table 1. The CLIC Management Group (chaired by Prof. Buffler, Director of CIRCLE) continue to hold regular conference calls to discuss issues related to data pooling, progress on proposed pooled analyses, amendment of authorship guidelines, and organization of the CLIC Annual Meeting. While waiting for complete data at the UC Berkeley institution, standardized procedures for quality control were developed and shared at the 2012 CLIC Workshop.

Table 1
Pooled Analyses	Lead Investigator	Institution	Status Since Last eport
Parental smoking, metabolizing genes, and risk of ALL	Infante-Rivard C.	McGill University, Montreal, Quebec, Canada	Data from 5 studies (Australia, France, US-California, Brazil, and Canada) were received and harmonized during the past year and are currently being analyzed.
Parental smoking, metabolizing genes and risk of AML and APL	Metayer C.	UC Berkeley, USA	Data from 7 studies (France, US-California, Greece, Costa Rica, New Zealand, UK) were received during the past year and are currently being harmonized. Data from 3 studies are outstanding (US-COG, Brazil, Germany).
Home pesticide use and risk of ALL & AML	Bailey H., Joachim Schüz	IARC, France	Data from 9 studies (France, US-California, US-COG, Greece, New Zealand, UK, Germany, Australia) were received during the past year and are currently being harmonized.
Geographical distribution of AML, APL and other cytogenetic subtypes	Zhang L.	UC Berkeley, USA	Expression of Interest (EOI) was submitted in June 2011 - Data delivery delayed into Year 4 due to competing requests listed above.
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.

A survey assessing the quality and completeness of cytogenetic data in CLIC studies was completed and presented at the 2011 CLIC Annual Meeting. Most cytogenetic data derive from conventional karyotyping while few studies used more sophisticated molecular biologic methods to detect gene transcripts using FISH and PCR assays. Also, cytogenetic data are not always available for all subjects within a study. Therefore, it is likely that subgroup analyses will be performed in limited CLIC study participants for which quality and completeness of cytogenetic data are adequate. Dr. Luoping Zhang conducted a literature review on the incidence of acute promyelocytic leukemia (a rare type of acute myeloid leukemia) worldwide.

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.

Statistical analyses are under way for parental smoking, xenobiotic genes and risk of ALL. Analyses on parental smoking and risk of AML and those on pesticide use and risk of ALL and AML will start shortly.

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.

Statistical analyses are under way for parental smoking, xenobiotic genes and risk of ALL. A survey assessing the availability of genotyping data in CLIC studies was completed and presented at the 2012 CLIC Workshop. The SNPs relevant to the other planned GxE analyses will be selected.

Specific Aim 5: Maintain the CLIC website http://clic.berkeley.edu to facilitate communication among CLIC members and outside communities.

The CLIC website was 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, including announcements of activities, events and forums, and a document posting and tracking system. Dedicated sections for CLIC Interest Groups, Logistic Groups, and Working Groups were added where group members post messages and documents to facilitate communication and exchange of ideas. Approved members have viewing, editing or administrative rights within these groups. Initial ground work in preparation for a centralized and dynamic meta-database repository containing an inventory of available study questionnaires, information on sample sizes, biospecimens, and data inventory has been started. It is anticipated that this resource will save significant time and effort in the conduct of pooled analyses.

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.

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.

During Year 3, we developed a method for extracting PCBs and PBDEs from 100 µL of whole blood, consistent with available quantities of blood from the childhood leukemia cases. The current analytical scheme consists of a liquid:liquid extraction followed by Florisil column clean-up, and analysis via high resolution gas chromatography-mass spectrometry (GCMS). Subsequently, we will validate the method using whole blood samples from anonymized adults.

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.

During Year 3, we used the analytical method developed in Years 1 and 2 to measure PAHs (12 analytes), PCBs (6 congeners) and PBDEs (22 congeners) in repeat dust samples from 204 households that had been measured at baseline (giving a total of 408 baseline and repeat samples available for statistical analyses). At present, all PAH measurements have been completed while PCBs and PBDEs are at the final stage of mass spectrometric analysis.

We used mixed-effects models of house-dust PAH concentrations to estimate variance components and identify sources of variability. For some PAHs [benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(a)pyrene, indeno(1,2,3-c,d)pyrene, dibenzo(a,h)anthracene, benzo(g,h,i)perylene] we observed a decreasing trend in PAH 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 PAH, substantial within-household variability was observed. Indeed, the variability in concentrations within a household (over time) was generally greater than the variability between households (across the population). We were able to identify several factors that explained some of the variability between households, including residents’ cigarette smoking habits, urban density, residence construction date, and residence type. A manuscript describing the mixed-effects modeling of house-dust PAH concentrations is being drafted. These same methods will be applied to dust measurements of PBDEs in Year 4.

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.

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 3, we continued efforts to modify a method developed in our lab for profiling HSA adducts in human serum (Li H, et al., 2011, Profiling Cys34 adducts of human serum albumin by fixed-step selected reaction monitoring. Mol Cell Proteomics, 10, M110 004606). This method was developed to detect HSA adducts in dried blood spots (DBS). This has proven difficult because of the small quantity of HSA available -- about 60 µg in a 3-mm DBS punch compared to 1 mg in a serum sample -- and the relatively complicated matrix (whole blood as compared to serum) and resulting interference of isobaric peptides. Thus, in addition to scaling down enzymatic digestion to account for the lower mass of HSA, and optimizing offline HPLC to minimize the collection volume, it also was necessary to remove undigested proteins and other peptides that interfered with adduct detection. In profiling experiments, using untargeted fixed-step selected reaction monitoring (SRM) mass spectrometry, we have detected 3 – 8 adducts in digests of proteins from 3-mm punches of DBS obtained from anonomyzed adults. Efforts to increase the number of detectable adducts are under way.

Specific Aim 4: Identify HSA adducts observed in profiles, paying particular attention to adducts associated with leukemia status and changes from birth to diagnosis.

Using a targeted liquid chromatography-SRM method, we have tentatively identified the sulfinic acid and sulfonic acid modifications on Cys34 and the Cys34-benzoquinone adduct in 3-mm DBS punches obtained from anonomyzed adults. These assignments were based on comparisons of characteristic peptide sequence tags and elution times with reference standards. Final confirmation of the identities of these adducts will require experiments with high-resolution mass spectrometry, which should be conducted soon.

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.

Aim 5a involves development of an assay that employs isotope-dilution mass spectrometry for quantitation of targeted adducts. During Year 4, we will react an isotopically-labeled T3 peptide with idodoacetamide to produce a suitable internal standard. By adding known quantity of this internal standard to tryptic DBS digests, we will be able to quantitate targeted Cys34 adducts (which reside on the T3 peptide). Aims 5b and 5c will be pursued during Year 4.

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.

R834511C003: 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 made extensive progress on this aim and have completed the processing of 8 fetal bone marrows, 238 leukemia bone marrow samples, and extensive analytical comparisons between the two. DNA was assessed using the Illumina HD450 array, and RNA was processed with Affymetrix ST1.0 arrays. This has resulted in one submitted publication with three more manuscripts in preparation. We have found that B-cell differentiation is primarily a demethylating phenomenon, with most methylation changes being a reduction in level. We also have processed the samples for gene expression, noting that most demethylation events are associated with increased expression of their corresponding gene targets. Methylation changes with B-cell differentiation are shown in Figure 1, which has been submitted for publication in a high impact journal.

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 completed, and we currently are performing extensive statistical analysis. We are assessing case-control differences in DNA methylation patterns, and the relationship of DNA methylation to environmental risk variables, as well as the DNA methylation characteristics of the leukemia bone marrows after the children had grown. We are examining the relationship of environmental variables among the controls only, and then assessing whether these interact with case status. An example of such an analysis is shown in Figure 2, which demonstrated that paternal smoking imparts a change in DNA methylation status in a number of loci. We currently are working towards replicating this association.

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.

This aim will be completed in the coming year. We are choosing a second set of Guthrie cards from leukemia cases and controls which also are derived from the California Childhood Leukemia study. Meanwhile, the IRB approvals for the larger replication set from the California archive have been obtained, and Guthrie samples have been requested from the Caifornia Department of Public Health in preparation for that work in the coming year.

Core A – Administrative Core

Specific Aim 1: Assist the Center Director in the daily planning, execution, and coordination of the Center.

Aim 1 is being met. Members of the Internal Advisory Committee including the Project and Core Directors, Pediatric Health Specialists, and the Junior Faculty Investigator meet monthly to discuss progress on all three Projects and Cores, as well as any additional needs for administrative support. Decision and action items are summarized in detailed minutes, to ensure timely follow-up. CIRCLE members participate in monthly NIEHS/EPA conference calls with investigators from other Centers.

The External Advisory Committee (EAC) has been selected and includes members with expertise in all the Center’s relevant areas of research and outreach: Andrea Hricko (USC/UCLA), David Martin (Children’s Hospital Oakland Research Institute), Terry Dwyer (Murdoch Children’s Research Institute), Rob McConnell (USC), Lauren Zeise (Cal EPA), Jorn Olsen (Danish National Birth Cohort), Elaine Faustman (University of Washington), Irva Hertz-Picciotto (University of California, Davis), and Paul Wise (Stanford). Drs. Dwyer and Faustman will not be able to attend the initial EAC meeting in September, and Kathleen Stewart (Region 9 EPA), is awaiting final authorization from the EPA legal department before officially accepting the invitation to join the EAC. The EAC will meet September 28-29, 2012. The annual meeting of the California Childhood Leukemia Study EAC (September 27-28) and the annual meeting of the Childhood Leukemia International Consortium (October 1-2) will be held in the same venue as the CIRCLE EAC to facilitate interactions and potential collaborations among childhood leukemia investigators.

Specific Aim 2: Provide scientific leadership for the overall Center.

The leader of the Research Translation and Community Outreach Core B (Amy Kyle), Project 3 Leader (Joseph Wiemels), Pediatric Health Specialist (Mark Miller) and Todd Whitehead (Project 2), represented CIRCLE at the 2012 Children’s Center Meeting in Bethesda, Maryland. Dr. Kyle served on the planning committee for the Partnerships for Environmental Public Health (PEPH) meeting that followed the CEHCs meeting.

Stephen Rappaport (Project 2 Leader) and Director of the Center for Exposure Biology at the University of California (UC), Berkeley, organized a workshop of the Standing Committee of the National Academies' Emerging Science for Environmental Health Decisions Committee in December 2011, and gave one of the two keynote addresses. The workshop examined “emerging technologies that can be used to gather individual exposure information based upon external and internal measurements… Recent proof of-concept studies were highlighted and bioinformatics tools… discussed.”

CIRCLE members represented CIRCLE at the Children with Cancer’s International Scientific Conference on Early Exposures and Childhood Cancer in London (April 24-26). Dr. Wiemels (Project 3 Leader) was an invited speaker. Drs. Buffler (PI), Metayer (Project 1 Leader), Chokkalingam (Project 3), and Whitehead (Project 2) proffered papers.

CIRCLE co-sponsored the Center for Children’s Environmental Health Network Conference in San Francisco on May 30-June 1, entitled, ”The Contribution of Epigenetics in Pediatric Environmental Health.”

Drs. Miller and Dahl (the Center’s Pediatric Health Specialists) conducted a pilot survey of knowledge and practices regarding possible environmental causes of childhood cancer with faculty and fellows in Pediatric Hematology/Oncology at Stanford. Pursuant to a series of discussion at Internal Advisory Committee meetings, and with the assistance and expertise of Dr. Metayer (Project 1), they developed a revised survey to determine what Pediatric Oncologists, Hematology/Oncology Fellows in training and nurse practitioners who care for children with leukemia consider when they are taking a history about the child with leukemia and their family. The survey will be distributed to all the physicians, nurse practitioners and Hematology/Oncology fellows who are practicing at centers that admit patients to the California Childhood Leukemia Study (CCLS) protocol (PI: Patricia Buffler), in the Salt Lake City, Utah region referral center and in the Dana Farber Children’s Cancer Consortium. Survey results will inform future efforts for training and education.

The Center’s Pediatric Health Specialists also contributed to refinement of the questionnaires being developed by Drs. Metayer and Buffler in the CCLS. For example, they participated in the redesign of the study questionnaire to include a method to assess the possible contribution of prenatal stress to leukemia risk as a risk modifier.

Dr. Morimoto (the Center’s Junior Faculty-Development appointee) continued her work with CLIC (Project 1); she took the lead in developing an interactive web-based data dictionary and sample size calculator hosted on the secure CLIC website to be used by CLIC investigators during the hypothesis generation phase of collaborative projects. She demonstrated this tool at the CLIC Annual Meeting in Barcelona, Spain (September 2011), and is working with Dr. Metayer to establish and support a more comprehensive CLIC data coordinating center. Dr. Morimoto was involved in leading CLIC-wide projects to characterize the type and amount of genetic and cytogenetic data collected by the different studies. She currently is leading the effort to compile an inventory of genotyped SNPs from each CLIC study (information that may be used, with proper consent by each study principal investigator, for immediate gene association and gene-environment interaction analyses).

In October 2011, Dr. Morimoto submitted an application for an Exploratory/Developmental Research Grant Award (R21) to NIH, titled “A Pilot Study of Childhood Leukemia in Guatemala,” to assess the feasibility of conducting a case-control study of childhood leukemia in Guatemala. Her initial application received a highly competitive impact/priority score of 18. Data generated from this pilot study will provide preliminary data for a later application for an independent R01. She is completing two manuscripts relevant to the genetic and environmental determinants of childhood leukemia. The first is a haplotype analysis examining the association of genetic variants in iron metabolism and risk of childhood ALL, as well as their interaction with iron exposure in the California Childhood Leukemia Study (CCLS) population. The second expands upon the results of her analysis of the validity of using maternal biospecimens to estimate early childhood environmental exposures using data from the CCLS, presented at the International Society for Environmental Epidemiology Annual Meeting in Barcelona, Spain (September 2011).

Specific Aim 3: Provide and maintain access to research data and specimens.

Material Transfer Agreements continue 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. IRB approval was received from both the State of California (Genetic Disease Branch, the California Cancer Registry, and the Genetic Disease Screening Program) and UC Berkeley for the Childhood Cancer Record Linkage Project (CCRLP). Creation of the CCRLP will facilitate the use of neonatal blood spots by Project 3 in achieving Specific Aim 3. Dr. Metayer (Project 1) selected cases and controls from the CCLS database and biorepository that Dr. Wiemels will use for the replication set. Dr. Metayer also is providing Dr. Rappaport (Project 2) with the same set of cases and controls that Project 3 will use in a replication study.

Significance

Core B – Research Translation and Outreach Core

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.

The RTOC continues to focus on topics identified in Year 2 (i.e., significance of social contact and possible role of infectious agents; impact of x-rays; exposure to chemicals, pre-conception and pre-natal periods; homes and dust as reservoirs; epigenetic mechanisms). The complexity of the research, with regard to subtypes of leukemia and the ways they can be characterized, presents challenges to audiences that are primarily interested in causes. Because such findings emerge gradually, we decided to include them in streams with other information in order to maintain audience interest. We did not engage a communications consultant, as originally planned, due to changes in the consultant’s organizational affiliation; instead we are conducting all tasks internally.

We completed the assessment of social media platforms and concluded that providing definitive content in video format is the best fit given our schedule and scope. In cooperation with the UC Berkeley Campus video unit, we are producing a series of videos. We are addressing the issues associated with public viewing of unpublished data and developing agreements governing intellectual property. We negotiated a fair agreement with UC Counsel, and continue to resolve some remaining issues. We are posting the video series at the UC Berkeley Channel on YouTube. Our Internal Advisory Committee (IAC) approved a web design with sections on research, investigators, publications, as well as modular pieces in short essay format written by investigators; these will be accessible to lay audiences and allow content development over time.

Dr. Kyle was active in the NIEHS Partnership for Environmental Public Health and presented a plenary lecture at the biennial conference in Washington. She was asked by NIEHS to serve on the planning committee, to chair a work group, and to lead three breakout discussions. The track organized by her group had the greatest interest among attendees. This advanced the knowledge base on theory and practice of research translation.

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 are highly successful. The PEHSU is presenting information to clinical audiences in collaboration with the pediatric oncology expert. CEHN is incorporating research findings into programs, communications, and educational resource materials including a web page with audience-specific fact sheets, posts via Twitter and Facebook, newsletter articles, and the article-of-the-month. CEHN is hosting a research conference on the Contributions of Epigenetics to Pediatric Environmental Health in May, and the connection to cancers and children's early life exposures will be part of the program.

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.

This activity is now scheduled for Year 5.

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.

As scheduled, an assessment of opportunities was conducted in Year 03 and will be discussed further with partners and the IAC before a decision is made and actions move forward in Year 4.

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.

CIRCLE collaborated with the Office of Environmental Health Hazard Assessment of Cal-EPA and the PEHSU at UCSF on a Pediatric Environmental Health Symposium in January 2012 for scientists and analysts at Cal EPA and CDPH, EPA Region 9 scientists, and non-governmental organizations, highlighting cutting edge research of CIRCLE and five other CEH Centers from the West Coast and PEHSUs at UCSF and University of Washington. The symposium received a very positive response; presentations were recorded for the web. Dr. Mark Miller was designated as state lead on children’s environmental health, and we will continue collaborating to support this.

Dr. Kyle remains engaged in briefing government representatives and others about the implications of chemicals policy for children, continuing her engagement with the California Green Chemistry Initiative and the development of the regulations and process for the Chemical Information Clearinghouse mandated in SB 509. She presented a poster at the 2011 meeting of the International Society for Environmental Epidemiology on these findings. Dr. Kyle was asked by the EPA Office of Children’s Health Protection to lead a work group of CHPAC. Following recommendations on screening of chemicals to address children in Year 2 was an analysis of actions to better address the pre-natal period in Year 3. 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.

Immediately following the January Symposium, a meeting organized by Drs. Kyle and Miller and attended by representatives of of six West Coast NIEHS/EPA funded Children’s Environmental Health Research Centers explored ways to collaborate on research translation and achieve synergies in collected data and expertise. The meeting held at the UC Berkeley CIRCLE offices elicited great interest in further collaboration and coordination on the research as well as on research translation. Areas of interest included possible sharing of samples, methods, policy, and synthesis of information. However, because all of the investigators are wholly occupied, strategic supplemental funding will likely be needed to achieve synergies.

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 this year illustrates the potential in using a networked model of research translation and outreach to reach a more diverse audience using existing channels rather than to try to create such channels de novo.

Future Activities:

R834511C001: Childhood Leukemia International Consortium Studies

Specific Aim 1: Continue data pooling and development of meta-database, and complete inventory of cytogenetic data. Organize the 2012 CLIC meeting in Berkeley (October 1-3) in conjunction with the 2012 External Advisory Committee Meeting for CIRCLE (September 28-29).

Specific Aim 2: Continue statistical analyses.

Specific Aim 3: Obtain CLIC cytogenetic data; compare ratios of childhood ALL/AML and APL/AML to those derived from population-based registries in corresponding countries.

Specific Aim 4: Continue statistical analyses.

Specific Aim 5: Continue website maintenance. Start to design and develop centralized data harmonization core.

R834511C002: Exposure Assessment for Childhood Leukemia

Specific Aim 1: Perform measurements of cotinine, PCBs, and PBDEs in serum samples and nicotine in dust samples.

Specific Aim 2: Complete analyses of PBDEs in archived and repeated dust samples.

Specific Aim 3: Continue to 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. Begin analysis of HSA adducts in DBS from childhood leukemia cases and 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 control children of smoking and nonsmoking mothers and childhood leukemia cases and controls.

R834511C003: Prenatal Exposures, DNA Methylation, & Childhood Leukemia

Specific Aim 1: We have completed this aim and will publish the results in the coming year.

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.

Specific Aim 3: We will perform a replication analysis this year on CCLS case/control cards. Additional cards from the California archive will be analyzed in future years.

Core A – Administrative Core

Specific Aim 1: Continue administrative and research support. Complete establishment of the Center External Advisory Committee, and schedule meeting. Establish the Center administrative database (e.g., contact information, fiscal data, and reports). Pediatric Health Specialists, Drs. Mark Miller and Gary Dahl, will continue short seminar series of environmental and genetic factors in childhood leukemia for clinicians.

Specific Aim 2: Continue coordination of scientific agenda. Participate in NIEHS monthly conference calls with investigators from other Centers.

Specific Aim 3: Continue support for data sharing and database maintenance

Core B – Research Translation and Outreach Core

Specific Aim 1: Continue to develop web content integrated with video content posted through the UC channel at YouTube or similar outlet and assess the impact of these efforts.

Specific Aim 2: Continue to roll out relevant messages by UCB, CEHN, and PEHSU investigators.

Specific Aim 3: Begin activity in Year 5.

Specific Aim 4: Decide about additional partners and recruit them.

Specific Aim 5: Organize second symposium on current research on children’s environmental health scheduled for January 2013, with a focus on cumulative impacts.

Specific Aim 6: Continue to support joint efforts among the western centers and PEHSUs, working toward joint research synthesis and translation, and seeking supplemental funding and hosting a second in-person meeting in January 2013.

Journal Articles: 13 Displayed | Download in RIS Format

Publications Views
Other center views:	All 52 publications	13 publications in selected types	All 13 journal articles

Publications
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) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: Wiley-Full Text HTML Exit Other: Wiley-Full Text PDF Exit
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) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: Blood-Full Text HTML Exit Other: Blood-Full Text PDF Exit
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) R836159 (2018) R836159 (2019) R836159C003 (2016)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: Taylor & Francis-Full Text HTML Exit Abstract: Taylor & Francis-Abstract Exit Other: Taylor & Francis-Full Text PDF Exit
Journal Article	Lee S-T, Xiao Y, Muench MO, Xiao J, Fomin ME, Wiencke JK, Zheng S, Dou X, de Smith A, Chokkalingam A, Buffler P, Ma X, Wiemels JL. A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network. Nucleic Acids Research 2012;40(22):11339-11351.	R834511 (2012) R834511 (2013) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: OUP-Full Text HTML Exit Other: OUP-Full Text PDF Exit
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) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: OUP-Full Text HTML Exit Other: OUP-Full Text PDF Exit
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) R834511 (2014) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: ResearchGate-Full Text PDF Exit Abstract: Epidemiology-Abstract Exit
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) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: Wiley-Full Text HTML Exit Other: Wiley-Full Text PDF Exit
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) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: ScienceDirect-Full Text HTML Exit Other: ScienceDirect-Full Text PDF Exit
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) R834511 (Final)	Abstract from PubMed Abstract: ACS-Abstract Exit
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) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: Wiley-Full Text HTML Exit Abstract: Wiley-Abstract Exit Other: Wiley-Full Text PDF Exit
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) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: MCP-Full Text HTML Exit Other: MCP-Full Text PDF Exit
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) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Abstract: Cancer Epidemiology-Abstract Exit
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) R834511 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Abstract: Blood Reviews-Abstract Exit Other: ScienceDirect-Abstract Exit

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

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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.

Grantee Research Project Results

2012 Progress Report: Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE)

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