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Tobacco smoking and inborn genetics: effects on leukemogenesis

Institution: University of Southern California
Investigator(s): Joseph Wiemels, PhD
Award Cycle: 2018 (Cycle 27) Grant #: 27IR-0032 Award: $1,215,889
Subject Area: Cancer
Award Type: High Impact Research Project Award

Initial Award Abstract

Researchers have identified a link between parental smoking and childhood leukemia. Historically, it looked like this link was mainly through paternal smoking, but we have recently shown that maternal smoking during pregnancy, as well as tobacco in the environment of a young child, is strongly linked to a certain type of genetic mutation in leukemia cells. This type of mutation, namely gene deletions, has been shown to occur in normal blood cells in neonates of mothers who use tobacco during pregnancy. We now therefore have a more clear idea the specific type of damage caused to children’s blood cells from tobacco. What we would like to do with this current research project is to determine which children in the population are susceptible to these mutations from tobacco by examining both the tobacco exposures and the inborn genetic code of the child together.

In our past work, we used questionnaires to assess parental smoking before, during, and after pregnancy. We asked these questions from parents after their child was diagnosed with leukemia (or for children the same age without disease, for comparison).  We know that some of this information is not very accurate, due to lack of recall from the parents or inaccurate reporting. We now have a different way to assess smoking during pregnancy. When someone uses tobacco, certain genes in our genome will respond by increasing expression. We are able to detect these “epigenetic” changes very accurately, and we now know that these changes are tightly linked to tobacco exposure levels. We will use this unbiased method to assess smoking in a very large childhood leukemia study. We already have complete genetic scans of all the participants of this study. We will use the grant finds to do the tobacco assessment, and analyze the tobacco and genetics together using a sophisticated “gene-environment” analytical method.

To put some numbers on this, we will study 6708 neonates in the California Cancer Records Linkage Project childhood leukemia genome-wide association study (GWAS). Half of the participants contracted leukemia (3263 leukemia cases) and the other half remained healthy (3445 controls). Then, we will replicate our most significant findings in an independent study, the California Childhood Leukemia Study (CCLS, 2378 subjects: 1273 cases and 1105 controls) which is an independent GWAS study and has both DNA methylation and self-report measures of maternal and household smoking.  Finally, we will assess whether the top replicating associations are related to the gene deletion phenotype which we previously linked to tobacco exposures. In this way we will be able to discover what vulnerabilities certain people have to tobacco, and will be able to directly link those vulnerabilities to a leukemia-inducing mechanism. 

In sum, this project will utilize a unique measure of smoking exposures, and very large California-specific population resources to explore the health effects of smoking on our most vulnerable population – young children. While treatments for leukemia have improved greatly over the years, we believe the best treatment is prevention, which remains our goal. This research study will lead us a long way to understanding mechanisms in tobacco-induced childhood leukemia and identify who is most susceptible.