1. 1 Childhood Leukemia International Consortium Childhood Leukemia International Consortium I4C – Barcelona - September 2011 Catherine Metayer, MD, PhD University of California, Berkeley University of California, Berkeley

2. 2 Outstanding Research Questions What are the critical windows of exposure? What are the critical windows of exposure? What are the risk factors of rarer CL subtypes like AML, APL, T-cell ALL? What are the risk factors of rarer CL subtypes 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?

3. 3 Timing of Exposure to Tobacco Smoke Pregnancy - Maternal smoking Postnatal - Child’s passive smoking exposure Preconception -Paternal smoking -Maternal smoking Birth INITIATIONPROMOTION

4. 4 Tobacco Smoke: Critical Windows of ExposureMaternalDirect (Germ Cell) Direct(Fetus)SecondhandPaternalDirect SecondhandSecondhand Others in Household SecondhandSecondhandSecondhand PRENATAL PRENATALPOSTNATAL ConceptionBirth

5. 5 Meta-analyses on Impact of Paternal Preconception Smoking on CL Source: Epidemiology of parental smoking and childhood leukemia: Kang et al., 2008

6. 6 Molecular Subsets of ALL INFANTSCHILDREN

7. 7 Translocations Associated with ALL: TEL-AML1 Gene Fusion Occurs in approximately 20-25% of patients with ALL (cALL) with peak incidence between ages 2 – 5 years. Occurs in approximately 20-25% of patients with ALL (cALL) with peak incidence between ages 2 – 5 years. Strong evidence that this occurs in utero. Strong evidence that this occurs in utero. Frequency of this translocation at birth is 100-fold greater than the risk of developing the corresponding leukemia. Frequency of this translocation at birth is 100-fold greater than the risk of developing the corresponding leukemia. Source: Greaves, BMJ, 2002.

8. 8 CLIC - 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-California Australia, France, Canada, and US-California 2007 First grant from the US National Cancer 2007 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 & MTHFR and risk of CL pooled analysis on folate & MTHFR 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)

9. 9 CLIC Mission Develop and support collaborations between scientists involved in CL research to accelerate knowledge on factors that influence the risk of childhood leukemia through epidemiological studies and related research Develop and support collaborations between scientists involved in CL research to accelerate knowledge on factors that influence the risk of childhood leukemia through epidemiological studies and related research Encourage free exchange of results (published or unpublished) and ideas in a collegial environment without fear of competition Encourage free exchange of results (published or unpublished) and ideas in a collegial environment without fear of competition

10. 10 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)

11. 11 CLIC 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 2011 Study period from mid-70’s to 2011 Common scientific interest Common scientific interest

12. 12 Website clic.berkeley.edu

13. 13 CLIC Interest Groups AML/APL AML/APL Environmental Exposure Environmental Exposure Family History Family History Genetics Genetics Infant Leukemia Infant Leukemia Infection and Immunity Infection and Immunity Occupational Exposures Occupational Exposures Outcomes Outcomes

14. 14 CLIC Procedures Call for Expression of Interest Full Proposal and Agreement of Pooled Analyses Data Transfer

15. 15 Ongoing Pooled Analyses Fetal growth and risk of childhood ALL Fetal growth and risk of childhood ALL Vitamin/folate supplementation before and during pregnancy, MTHFR variants and risk of childhood ALL and AML Vitamin/folate supplementation before and during pregnancy, MTHFR variants and risk of childhood ALL and AML Parental smoking, NQ01 gene, and risk of childhood ALL Parental smoking, NQ01 gene, and risk of childhood ALL

16. 16 Proposed Pooled Analyses Markers of childhood infections and allergies and of ALL Markers of childhood infections and allergies and of ALL Geographical of distribution of AML cytogenetic type, including APL Geographical of distribution of AML cytogenetic type, including APL Indoor sources of benzene and other hydrocarbons (i.e., parental smoking, home use of paint/solvent, type of heating), NQ01 gene, and risk of AML Indoor sources of benzene and other hydrocarbons (i.e., parental smoking, home use of paint/solvent, type of heating), NQ01 gene, and risk of AML

17. 17 Proposals Under Development Residential use of pesticides and risk of childhood ALL and AML Residential use of pesticides and risk of childhood ALL and AML Residential use of paint/solvent and risk of childhood ALL Residential use of paint/solvent and risk of childhood ALL SES, environmental and genetic determinants and CL survival in CLIC studies SES, environmental and genetic determinants and CL survival in CLIC studies

18. 18 Challenges Study specificity regarding prevalence of exposure, design, confounders (SES, ethnicity, etc…) Study specificity regarding prevalence of exposure, design, confounders (SES, ethnicity, etc…) Meta-data analyses vs. pooling of raw data Meta-data analyses vs. pooling of raw data Recognize potential for selection bias in observational studies that require subject consent, and attempt to assess the representativeness of participating families Recognize potential for selection bias in observational studies that require subject consent, and attempt to assess the representativeness of participating families

19. Pooling of Vitamin/Folate data (7624 cases/11459 controls)

20. Study Period and Vitamin/Folate Recommendation WHO recommendation of 0.4mg/day of folate

21. Prevalence of Vitamin Use

22. Prevalence of Folate Use

23. 23 CLIC Database Infrastructure Web-based inventory under development Web-based inventory under development Surveys for availability of biospecimen, genetic, and cytogenetic data Surveys for availability of biospecimen, genetic, and cytogenetic data Seek additional funding to complete and maintain CLIC inventory, centralized database of common variables, and data repository Seek additional funding to complete and maintain CLIC inventory, centralized database of common variables, and data repository

24. 24 Opportunities of Collaborations Between CLIC and I4C Exchanges of ideas Exchanges of ideas Genetic and epigenetic studies Genetic and epigenetic studies Emerging hypotheses such as parental smoking Emerging hypotheses such as parental smoking Exposure assessment in cohort studies that could inform case-control studies Exposure assessment in cohort studies that could inform case-control studies Ethical issues Ethical issues Exchanges of procedures Exchanges of procedures Standardize data Standardize data Compile background information on exposure pattern by country and overtime Compile background information on exposure pattern by country and overtime

25. 25 Acknowledgments Pat Buffler and colleagues at the UC Berkeley- based California Childhood Leukemia Study Pat Buffler and colleagues at the UC Berkeley- based California Childhood Leukemia Study Colleagues at CLIC, especially other founding Members L. Milne (Australia), C. Infante-Rivard (Canada), and J. Clavel (France) Colleagues at CLIC, especially other founding Members L. Milne (Australia), C. Infante-Rivard (Canada), and J. Clavel (France) Colleagues and sponsors at the National Cancer Institute Colleagues and sponsors at the National Cancer Institute Other sponsors in the US (NIEHS, EPA) and UK (Children with Cancer) Other sponsors in the US (NIEHS, EPA) and UK (Children with Cancer) Families and clinicians Families and clinicians

26. 26 Thank you