Birthweight & Childhood Leukaemia: Results from pooled analyses

1. Birthweight & Childhood Leukaemia: Results from pooled analyses Tracy Lightfoot Epidemiology & Cancer Statistics Unit Department of Health Sciences University of York

2. In utero origins of leukaemia • Evidence childhood leukaemia originates in utero. • Chromosomal translocations such as t(12;21), t(4;11), or t(8;21) are found at birth in children who later develop leukaemia. • Indicative that prenatal exposures may be important in leukaemogenesis

3. Aetiology of childhood leukaemia • Known risk factors • Age • Sex • Trisomy 21

4. Aetiology of childhood leukaemia • Known risk factors • Age • Sex • Trisomy 21 • Consistent observations • Genetic variants IKZF1(7p12.2), CDKN2A/CDKN2B(9p21), ARID5B(10q21.2), CEBPE(14q11.2) • Heavy birthweight (> 3500, 4000 or 4500g)

5. Previous meta-analysis • 18 studies conducted between 1962-2002 • 10282 children - 5281 ALL cases • OR 1.26 (95% CI 1.17-1.37) (≥4,000 g vs. <4,000 g) • 14% increase in risk of ALL per 1000g increase in birthweight

6. Additional observations • Findings similar for B-cell ALL and T-cell ALL and individuals subtypes (Hjalgrimet al., 2004; O’Neil et al., 2012) • Suggest determinants are not risk factors for a specific type of ALL • Children with ALL have the same birthweight as their siblings (Hjalgrim et al., 2004 and Smith et al., 2010)

7. Questions still to answer? • What’s the relationship between ALL and fetal growth across the gestational age spectrum? • What’s the relative importance of a baby’s absolute weight/size at birth versus the rate of fetal growth?

8. Potential issues….. Rare events: • ALL accounts for less than 0.5% of all incident cancers • Less than 1% of live births weighing < 1500g, and only 1-3% weight above 4500g. • Most investigations concentrate on high birthweight, either dichotomizing their data (e.g. <4000g versus ≥ 4000g) or using relatively conservative cut-points (e.g. <2500g, 2500-3999g, ≥ 4000g). Self-reported data: • Many of the case-control studies on this topic have relied on birth characteristics reported by mothers at interview, (potential for maternal recall bias)

9. Recent studies • Pooled analyses from Germany, UK and USA • started 2001 – published 2013 • 4075 cases and 12065 controls • Pooled analyses from CLIC • Started 2009 – published 2013 • 7348 cases and 12489 controls (12 studies) • 1680 cases and 3139 controls POBW

12. Individual countries and pooled birthweight distributions

13. US, UK and Germany pooled birth weight distribution by gestational age

14. Birthweight and ALL

18. Study population • Children (≤ 15 years) registered for primary care with a General Practitioner (GP) • Cases - ascertained from multiple sources • Treating/referring hospitals • Cross-checks with cancer registries • Controls – 2 per case from primary care population registers, individually matched on:- • date of birth • sex • UKCCS region of residence Linked to primary care and maternity records, registration and census data, birth and death certificates for all cases and controls irrespective of participation in the study

19. UK BWT interview versus birth certificates

20. Gestational Age

21. Gestational age

22. UK control data

23. Summary • Children with ALL were, on average, heavier than controls at all gestations • Overall, a 1.2 (95% CI 1.1-1.3) increase in ALL risk per kg increase in birthweight was observed • driven by a deficit of low-birthweight at all gestations and an excess of high-birthweight at ≥ 40 weeks. • Stable relationship within age strata (< 1, 1-4, 5-9 and 10-14 years) is noteworthy and is in accord with other studies that have presented age-specific data. • Confirms association with size at birth is not restricted to infants, as had originally been suggested

24. Conclusions • Importance of looking across full birthweight spectrum when examining associations with disease risk. • For the first time identified marked paucity of very low-birthweight babies (< 1500g) among ALL cases at all gestational ages; • given in-utero origins of ALL presence of disease at birth could act to increase perinatal mortality in this immature and vulnerable group?

26. Map of Childhood Leukemia Studies participating in CLIC 9,10,11 13 6,7 12 1 14 4 15 2 3 16 5 8 17 18 Pooled analysis : California State, USA, COG, USA, Canada; Brazil; UK, France (x3), Germany; Greece, Australia, New Zealand.

27. Fetal growth and childhood acute lymphoblastic leukemia: LGA v AGA OR 1.24 95% CI (1.13-1.36)

29. Proportion of Optimal Birthweight • Takes into account mothers height (cm), birthorder, sex, birthweight (g) and gestational age

30. Fetal growth and childhood acute lymphoblastic leukemia: POBW OR 1.16 95% CI (1.09-1.24)

32. Summary • Accelerated fetal growth associated with increased risk of ALL irrespective of high birth weight. • Effect consistent whether using categorical or continuous measure of growth.

33. Mechanisms??????? • Links with other childhood/adults cancers • ↑ IGF1 levels • Drives pre-leukaemic cells towards leukemogenesis • Pre-leukaemic cells have higher IGF-1 levels leading to higher birthweight • Not supported by sibling birthweight observations • Factors governing IGF levels e.g. PAPP-A • In utero levels of estrogens • Increased numbers of stem cells • ???????????????????

34. Acknowledgements • Eve Roman • Alex Smith • Michele R Forman • Martha S Linet • Les Robison • Jill Simpson • Peter Kaatsch • KathrineGrell • Kirsten Frederiksen • Joachim Schüz • Clinicians/Health Professionals • Funders • Families… • Elizabeth Milne • Kathryn R. Greenop • Catherine Metayer • EleniPetridou • Maria S. Pombo-de-Oliveira • Claire Infante-Rivard • John D. Dockerty • Logan Spector • SérgioKoifman • Laurent Orsi • JérémieRudant • Nick Dessypris • Margarita Baka • Alessandra Faro • Bruce K. Armstrong • Jacqueline Clavel • Patricia A. Buffler