Childhood Leukemia International Consortium

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

2. Outstanding Research Questions • What are the critical windows of exposure? • 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. Timing of Exposure to Tobacco Smoke Preconception -Paternal smoking -Maternal smoking Pregnancy - Maternal smoking Postnatal - Child’s passive smoking exposure Birth INITIATION PROMOTION

4. Tobacco Smoke: Critical Windows of Exposure Conception Birth

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

6. Molecular Subsets of ALL INFANTS CHILDREN

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. • 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. Source: Greaves, BMJ, 2002.

8. CLIC - History • 2005 Meeting at IARC to introduce the concept • 2006 First informal meeting with PIs from Australia, France, Canada, and US-California • 2007 First grant from the US National Cancer Institute to support the proof of principle of pooled analysis on folate & MTHFR and risk of CL • >2007 Additional support from the Children with Cancer, UK & the NIEHS and EPA, US (since 2009)

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leukemia through epidemiological studies and related research • Encourage free exchange of results (published or unpublished) and ideas in a collegial environment without fear of competition

10. 22 CLIC Studies UKCCS(Roman) Manchester, UK(Birch/Taylor) CCRG, UK(Murphy) GCCR(Kaatsch/Schüz) Germany(Grosche, Ziegelberger) Italy(Magnani) Japan(Manabe, Mizutani) NCCLS(Buffler) COG(Spector) Texas(Bondy) Greece(Petridou) Quebec(Infante-Rivard) St. Justine(Sinnett) France(Clavel) Seoul(Kang) Costa Rica(Monge) Brazil-IAL(Pombo-de-Oliveira) AUS-ALL(Armstrong/Milne) New Zealand(Dockerty) 22 Studies, 13 Countries Red = New Member Countries in 2009 Green = Countries in planning phase to start study on childhood leukemia

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

12. Website clic.berkeley.edu

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

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

15. Ongoing Pooled Analyses • Fetal growth and risk of childhood ALL • 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

16. Proposed Pooled Analyses • Markers of childhood infections and allergies and of ALL • 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

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

18. Challenges • Study specificity regarding prevalence of exposure, design, confounders (SES, ethnicity, etc…) • 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

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. CLIC Database Infrastructure • Web-based inventory under development • 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

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

25. Acknowledgments • 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 and sponsors at the National Cancer Institute • Other sponsors in the US (NIEHS, EPA) and UK (Children with Cancer) • Families and clinicians

26. Thank you