CIRCLE investigators translate research for pediatricians, emphasize importance of efforts to prevent childhood leukemia.

There is a perception among the medical community at large and among pediatricians in particular, that the causes of childhood cancer are completely mysterious.  However, in contrast to most other pediatric cancers, there is growing evidence that several environmental hazards increase the risk of childhood leukemia.  Despite the strength of the existing proof, the dissemination of this knowledge to clinicians has been limited.

In an effort to bring pediatricians up-to-speed on the currently-accepted risk factors for childhood leukemia and to encourage a discourse that would lead to childhood leukemia prevention programs, CIRCLE investigators Catherine Metayer, Gary Dahl, Joe Wiemels, Todd Whitehead, Amanda Singer, and Mark Miller recently published two journal articles: “Childhood Leukemia: A Preventable Disease” (published in the November issue of Pediatricsand “Childhood Leukemia and Primary Prevention” (published in the October issue of Current Problems in Pediatric and Adolescent Health Care).

CIRCLE investigators have been at the forefront of identifying environmental causes of childhood leukemia, including through their leadership roles in the Childhood Leukemia International Consortium.  The Consortium has demonstrated the risk of developing childhood leukemia is consistently positively associated with exposures to solvents, traffic, pesticides, and tobacco smoke in studies from all over the world. Likewise, the intake of vitamins and folate supplementation during the preconception period or pregnancy has been demonstrated to have a protective effect.

CIRCLE investigators have also shown that some children may be more vulnerable to leukemia than others, as documented by the high and increasing incidence of childhood leukemia in California Latinos.

In their reviews, the authors argue that it would be prudent to establish cancer-prevention programs that are designed to limit exposure to existing leukemia risk factors. They suggest prevention programs are particularly warranted because the same environmental exposures that have been implicated as risk factors for childhood leukemia also cause other serious health outcomes.

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CIRCLE investigators show how the inherited genetic code determines the impact that prenatal exposure to toxins has on DNA methylation in newborns.

Environmental exposures are known to influence epigenetics by introducing modifications to the outer surface of a DNA molecule that turn gene expression “on” or “off.”  Epigenetic changes can lead to negative health outcomes and they likely play a role in the development of childhood leukemia.  It is during periods of development, especially during the in utero period, that we are most vulnerable to epigenetic alterations.  For example, it has been previously observed that maternal smoking during pregnancy results in a very specific pattern of DNA methylation changes.

Up until now, however, it has been unclear what role the inherited genetic code plays in the relationship between environmental exposures and their resulting epigenetic modifications.  For example, does prenatal exposure to cigarette smoking impact the epigenetic landscape in basically the same way for every newborn?  Or does there exist a genetically-predisposed population that is especially vulnerable to smoking-induced epigenetic disturbances?

CIRCLE investigators Semira Gonseth-Nussle, Adam de Smith, Ritu Roy, Mi Zhou, Juhi Ojha, Catherine Metayer, and Joe Wiemels addressed these questions in their paper, “Genetic contribution to variation in DNA methylation at maternal smoking-sensitive loci in exposed neonates,” which was published in the September issue of the journal Epigenetics.

The investigators examined whether methylation levels at 10 DNA sites previously associated with prenatal maternal smoking were associated with individual genetic variation at the genome-wide level. Genome-wide association tests were performed in 736 case and control participants of the California Childhood Leukemia Study. Three of the DNA sites where methylation changes were strongly associated with maternal smoking also demonstrated a strong association with genetic polymorphisms located nearby: cg18146737 in the GFI1 gene with rs141819830 , cg05575921 in the AHRR gene with rs148405299, and cg12803068 in the MYO1G gene with rs61087368.  These associations were strongly statistically significant even after accounting for multiple comparisons.  For one of these methylation sites (cg18146737 near GFI1 gene), an association between maternal smoking and DNA methylation changes was only apparent after accounting for the genotype.

The authors’ results suggest that future epigenome-wide association studies seeking to relate environmental exposures to DNA methylation alterations must adequately and routinely account for the influence of genetics to avoid potential confounding.

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