1. M. Tevfik DORAK Environmental & Occupational Health College of Public Health Gender Effect in Cancer Risk Pediatric Cancer Epidemiology: Fundamental Questions & Strategies Epigenetics and Early Life Exposures in Cancer Risk Houston, May 13, 2010

2. Magnitude of Gender Effect in Cancer, Childhood Cancer and Childhood Leukemia Gender-specific Genetic Associations in Childhood Leukemia Possible Mechanisms of the Gender Effect in Childhood Leukemia Fetal exposure to Iron and Childhood Leukemia Risk Strategies to Study Gender Effect in Childhood Cancer Outline

3. SEER, 1975-1995 Magnitude of Gender Effect in Cancer

5. Gender-specific Genetic Associations in Childhood Leukemia HLA complex HLA-DRB4, -DQA1, -B67, HSPA1B Immune regulatory genes IRF4 Xenobiotic enzymes CYP1A1, NAT1, (NQO1) DNA repair genes XRCC1, APEX1, MSH3 Iron regulatory genes HFE/TFRC Latest GWAS data were not analyzed for sex-specific associations!

6. Functional study of the IRF4 risk marker suggested the involvement of NF-kB pathway and estrogen

8. The association with earlier age-at-onset was observed only in females, as has been noted also in adult cancers. This effect is attributed to the effect of estrogen. The associations of IRF4 and MDM2 implicate estrogen action in childhood ALL and raises the possibility of mediation of fetal programming of childhood ALL susceptibility by sex hormones. Fetal programming of adult disease susceptibility has been shown in several diseases and equally applies to childhood leukemia. MDM2 SNP309 is associated with earlier age-at-onset in leukemia as in breast cancer

9. Possible Mechanisms of the Gender Effect in Cancer Sex Hormones Thyroid follicular cancer is more common in females. Males may be protected due to androgen receptor expression in thyroid follicular cells through which androgens reduce proliferation of follicular cells. Liver cancer is less common in females. Estrogens inhibit secretion of IL-6, a key mediator of liver cancer development, and females are protected owing to estrogen effect. Sex hormones also modify the immune system and males, on average, have lower immune capacity. Males suffer from more infections and cancers (lower immune surveillance?)

10. Possible Mechanisms of the Gender Effect in Cancer Non-immune

11. Possible Mechanisms of the Gender Effect in Childhood Leukemia Higher cell proliferation rate in males Lower immune system capacity Fetal exposure to sex hormones Epigenetics Xenobiotic enzyme activity difference between the sexes Higher radiosensitivity of lymphocytes in males In animals: Males have higher sensitivity to oxidative damage, mutagen- and radiation-induced carcinogenesis

12. Early Life Exposure to Iron and Childhood Leukemia Risk HFE variants interact with a TFRC variant and show gene-dosage effect P = 0.02 HFE variants are associated with birth weight with sex effect and maternal effect, and in interaction with TFRC

13. Early Life Exposure to Iron and Childhood Leukemia Risk Cord blood iron levels correlate with HFE / TFRC genotypes in boys only X X - Maternal-fetal iron transport dynamics may differ in male and female pregnancies - Iron overload associated genotypes increase birth weight in males, and leukemia risk in males and females - Leukemia associations are stronger in females - We postulate that (1) females cannot offset iron excess by increasing their weight, (2) the high risk genotype combinations result in extreme iron levels in males and cause very high birth weight and high leukemia risk.

14. Conclusions Gender effect exists in childhood leukemia Sex-specific associations are masked unless specifically explored Gender effect may be due to fetal exposure to sex hormones, epigenetic changes or other mechanisms

15. Strategies to Study Gender Effect in Childhood Cancer Conclusive studies of gender effect require large sample sizes. Existing consortia (CLICK, I4C) or large studies (NCCLS, COG) can be used to unravel even weak gender effect. Genetic (SNP) studies should be expanded to epigenetics in light of the obvious gender effect. Stratification by sex should be encouraged in the analysis of childhood cancer studies. Case-only design is preferable to case-control design and may be the only choice in epigenetic studies.