M. Tevfik DORAK Environmental & Occupational Health

College of Public Health

Gender Effect in Cancer Gender Effect in Cancer Risk Risk

Pediatric Cancer Epidemiology: Fundamental Questions & Strategies

“Epigenetics and Early Life Exposures in Cancer Risk”Houston, May 13, 2010

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

SEER, 1975-1995

Magnitude of Gender Effect in Cancer

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!

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

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

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

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?)

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

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

Early Life Exposure to Iron and Childhood Leukemia Risk

HFE variants interact with a TFRC variant and show

gene-dosage effect

P =

0.0

2

HFE variants are associated with birth weight with sex effect and maternal effect, and in interaction

with TFRC

Early Life Exposure to Iron and Childhood Leukemia Risk

Cord blood iron levels correlate with HFE / TFRC genotypes in boys only

XX

- 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.

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

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.