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Childhood Childhood Leukemia Leukemia

International International ConsortiumConsortium

I4C – Barcelona - September 2011I4C – Barcelona - September 2011

Catherine Metayer, MD, PhDCatherine Metayer, MD, PhD University of California, BerkeleyUniversity of California, Berkeley

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Outstanding Research Outstanding Research QuestionsQuestions

What are the critical windows of exposure?What are the critical windows of exposure? What are the risk factors of rarer CL subtypes What are the risk factors of rarer CL subtypes

like AML, APL, T-cell ALL?like AML, APL, T-cell ALL? Are the risk factors specific to CL cytogenetic/

molecular subtypes of ALL and AML, or other tumor characteristics?

What is the contribution of GxE interaction?

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Timing of Exposure to Tobacco Smoke

PregnancyPregnancy- Maternal smoking- Maternal smoking

Postnatal- Child’s passive

smoking exposure

Preconception-Paternal smoking

-Maternal smoking

Birth

INITIATION PROMOTION

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Tobacco Smoke: Critical Windows of Exposure

MaternalMaternalDirect Direct

(Germ Cell)(Germ Cell)Direct Direct (Fetus) (Fetus)

SecondhandSecondhand

PaternalPaternalDirectDirect

(Germ Cell)(Germ Cell)SecondhandSecondhand SecondhandSecondhand

Others in Others in HouseholdHousehold

SecondhandSecondhand SecondhandSecondhand SecondhandSecondhand

PRENATALPRENATAL POSTNATALPOSTNATAL

Conception Birth

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Meta-analyses on Impact of Meta-analyses on Impact of Paternal Preconception Smoking Paternal Preconception Smoking

on CLon CL

Source: Epidemiology of parental smoking and childhood leukemia: Kang et al., 2008

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Molecular Subsets of ALL

INFANTS CHILDREN

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Translocations Associated with ALL: TEL-AML1 Gene Fusion

Occurs in approximately 20-25% of patients with Occurs in approximately 20-25% of patients with ALL (cALL) with peak incidence between ages 2 ALL (cALL) with peak incidence between ages 2 – 5 years.– 5 years.

Strong evidence that this occurs Strong evidence that this occurs in utero.in utero. Frequency of this translocation at birth is 100-Frequency of this translocation at birth is 100-

fold greater than the risk of developing the fold greater than the risk of developing the corresponding leukemia.corresponding leukemia.Source: Greaves, BMJ, 2002.

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CLIC - HistoryCLIC - History 2005 Meeting at IARC to introduce the concept 2005 Meeting at IARC to introduce the concept

2006 First informal meeting with PIs from 2006 First informal meeting with PIs from Australia, France, Canada, and US-CaliforniaAustralia, France, Canada, and US-California

2007 First grant from the US National Cancer2007 First grant from the US National Cancer Institute to support the proof of principle of Institute to support the proof of principle of pooled analysis on folate & pooled analysis on folate & MTHFRMTHFR and risk of CL and risk of CL

>2007 Additional support from the Children with Cancer, UK >2007 Additional support from the Children with Cancer, UK & the NIEHS and EPA, US (since 2009)& the NIEHS and EPA, US (since 2009)

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CLIC MissionCLIC Mission

Develop and support collaborations between Develop and support collaborations between scientists involved in CL research to accelerate scientists involved in CL research to accelerate knowledge on factors that influence the risk of knowledge on factors that influence the risk of childhood leukemia through epidemiological childhood leukemia through epidemiological studies and related research studies and related research

Encourage free exchange of results (published Encourage free exchange of results (published or unpublished) and ideas in a collegial or unpublished) and ideas in a collegial environment without fear of competition environment without fear of competition

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22 CLIC Studies

22 Studies, 13 Countries

NCCLS(Buffler)

COG(Spector)

Texas(Bondy)

Brazil-IAL(Pombo-de-Oliveira) AUS-ALL

(Armstrong/Milne)

New Zealand(Dockerty)

Seoul(Kang)

UKCCS(Roman)

Manchester, UK(Birch/Taylor)

CCRG, UK(Murphy)

Quebec(Infante-Rivard)

St. Justine(Sinnett)

GCCR(Kaatsch/Schüz)

Germany(Grosche, Ziegelberger)

Italy(Magnani)

France(Clavel)

Costa Rica(Monge)

Greece(Petridou)

Red = New Member Countries in 2009

Green = Countries in planning phase to start study on childhood leukemia

Japan(Manabe, Mizutani)

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CLIC StudiesCLIC Studies

~10,000 leukemia cases and 15,000 controls~10,000 leukemia cases and 15,000 controls ~50% studies with biospecimens~50% studies with biospecimens Study period from mid-70’s to 2011Study period from mid-70’s to 2011 Common scientific interest Common scientific interest

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Website clic.berkeley.eduWebsite clic.berkeley.edu

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CLIC Interest GroupsCLIC Interest Groups

AML/APLAML/APL Environmental ExposureEnvironmental Exposure Family HistoryFamily History GeneticsGenetics Infant LeukemiaInfant Leukemia Infection and ImmunityInfection and Immunity Occupational ExposuresOccupational Exposures Outcomes Outcomes

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CLIC ProceduresCLIC Procedures

Call for Expression of Interest

Full Proposal and Agreement of Pooled Analyses

Data Transfer

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Ongoing Pooled AnalysesOngoing Pooled Analyses

Fetal growth and risk of childhood ALLFetal growth and risk of childhood ALL

Vitamin/folate supplementation before and Vitamin/folate supplementation before and during pregnancy, during pregnancy, MTHFRMTHFR variants and risk of variants and risk of childhood ALL and AMLchildhood ALL and AML

Parental smoking, NQ01 gene, and risk of Parental smoking, NQ01 gene, and risk of childhood ALLchildhood ALL

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Proposed Pooled Proposed Pooled AnalysesAnalyses

Markers of childhood infections and allergies Markers of childhood infections and allergies and of ALLand of ALL

Geographical of distribution of AML Geographical of distribution of AML cytogenetic type, including APLcytogenetic type, including APL

Indoor sources of benzene and other Indoor sources of benzene and other hydrocarbons (i.e., parental smoking, home use hydrocarbons (i.e., parental smoking, home use of paint/solvent, type of heating), NQ01 gene, of paint/solvent, type of heating), NQ01 gene, and risk of AMLand risk of AML

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Proposals Under Proposals Under DevelopmentDevelopment

Residential use of pesticides and risk of Residential use of pesticides and risk of childhood ALL and AMLchildhood ALL and AML

Residential use of paint/solvent and risk of Residential use of paint/solvent and risk of childhood ALLchildhood ALL

SES, environmental and genetic determinants SES, environmental and genetic determinants and CL survival in CLIC studiesand CL survival in CLIC studies

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Challenges Challenges

Study specificity regarding prevalence of Study specificity regarding prevalence of exposure, design, confounders (SES, ethnicity, exposure, design, confounders (SES, ethnicity, etc…)etc…)

Meta-data analyses vs. pooling of raw dataMeta-data analyses vs. pooling of raw data

Recognize potential for selection bias in Recognize potential for selection bias in observational studies that require subject observational studies that require subject consent, and attempt to assess the consent, and attempt to assess the representativeness of participating familiesrepresentativeness of participating families

Pooling of Vitamin/Folate data

(7624 cases/11459 controls)

393 409790

300764 903 1033

121

997

1914

1249 790

579

1684

2458

10261226

1987

160303

0500

10001500200025003000350040004500

Australia

Brazil

Canad

a

Costa Rica

France

German

y

Greece

New Ze

aland

United St

ates -

- CCLS

United St

ates -

- COG

Controls

Cases

Study Period and Vitamin/Folate

RecommendationWHO recommendation of 0.4mg/day of folate

Prevalence of Vitamin Use

Prevalence of Folate Use

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CLIC Database CLIC Database Infrastructure Infrastructure

Web-based inventory under developmentWeb-based inventory under development Surveys for availability of biospecimen, Surveys for availability of biospecimen,

genetic, and cytogenetic datagenetic, and cytogenetic data Seek additional funding to complete and Seek additional funding to complete and

maintain CLIC inventory, centralized database maintain CLIC inventory, centralized database of common variables, and data repositoryof common variables, and data repository

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Opportunities of Opportunities of Collaborations Collaborations

Between CLIC and I4CBetween CLIC and I4C Exchanges of ideasExchanges of ideas

Genetic and epigenetic studies Genetic and epigenetic studies Emerging hypotheses such as parental smokingEmerging hypotheses such as parental smoking Exposure assessment in cohort studies that could Exposure assessment in cohort studies that could

inform case-control studiesinform case-control studies Ethical issuesEthical issues

Exchanges of proceduresExchanges of procedures Standardize dataStandardize data Compile background information on exposure Compile background information on exposure

pattern by country and overtimepattern by country and overtime

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AcknowledgmentsAcknowledgments Pat Buffler and colleagues at the UC Berkeley-Pat Buffler and colleagues at the UC Berkeley-

based California Childhood Leukemia Studybased California Childhood Leukemia Study Colleagues at CLIC, especially other founding Colleagues at CLIC, especially other founding

Members L. Milne (Australia), C. Infante-Rivard Members L. Milne (Australia), C. Infante-Rivard (Canada), and J. Clavel (France)(Canada), and J. Clavel (France)

Colleagues and sponsors at the National Cancer Colleagues and sponsors at the National Cancer Institute Institute

Other sponsors in the US (NIEHS, EPA) and UK Other sponsors in the US (NIEHS, EPA) and UK (Children with Cancer)(Children with Cancer)

Families and clinicians Families and clinicians

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Thank youThank you