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M. Tevfik DORAK Environmental & Occupational Health College of Public Health

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

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M. Tevfik DORAK Environmental & Occupational Health College of Public Health

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

  2. Outline • 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

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

  4. 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!

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

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

  7. MDM2 SNP309 is associated with earlier age-at-onset in leukemia as in breast cancer 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.

  8. 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?)

  9. Possible Mechanisms of the Gender Effect in Cancer “Non-immune”

  10. 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

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

  12. Early Life Exposure to Iron and Childhood Leukemia Risk Cord blood iron levels correlate with HFE / TFRC genotypes in boys only - 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. X X

  13. 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

  14. 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.

  15. ACKNOWLEDGMENTS Children with Leukaemia (London, UK) HUMIGEN, The Institute for Genetic Immunology (NJ, USA) Florida International University, College of Public Health

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