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Prenatal tobacco smoke exposure and somatic alterations in c

Institution: University of California, San Francisco
Investigator(s): Adam De Smith, Ph.D.
Award Cycle: 2017 (Cycle 26) Grant #: 26IR-0005 Award: $166,601
Subject Area: Environmental Exposure/Toxicology
Award Type: High Impact Research Project Award
Abstracts

Initial Award Abstract

Acute lymphoblastic leukemia, or ALL, is a cancer of the immune system and is the most common cancer in children under the age of 15. Although the cure rates for ALL are now high, the toxic effects of chemotherapy treatment that children have to endure may lead to adverse health effects in later life. It is crucial, therefore, that we identify the causes of childhood ALL so that we may be able to prevent this disease. The development of ALL is thought to begin in the womb with an initial mistake, or “mutation”, in the DNA of a child’s immune cell. This early cancer cell then has to acquire additional mutations to develop into full-blown leukemia. These mutations may include the “deletion” of important sections of DNA, i.e. genes, which normally protect against leukemia. It has previously been shown that a mother’s increased exposure to tobacco smoke during pregnancy is associated with an increase in the number of DNA deletions found in the developing child’s immune cells, which hints at a role for tobacco smoke in ALL. Furthermore, these tobacco-associated deletions appeared to be caused by a specific mechanism, called “RAG recombination”, which normally works in our bodies to create the variety of antibodies needed in our immune system. Mistakes in “RAG recombination” are also thought to cause the deletions that are acquired in early leukemia cells and that may lead to full-blown ALL. The presence of RAG-related deletions in both the immune cells of children whose mothers were exposed to tobacco smoke and in the leukemia cells of children with ALL suggests that maternal smoking during pregnancy may increase a child’s risk of developing ALL. This hypothesis forms the basis of our proposed study. We have previously analyzed a group of 525 children with ALL and were excited to find that those children whose mothers reported to have smoked during pregnancy had a significantly higher number of gene deletions in their leukemia cells. In addition to these results from “self-reported” smoking data, we confirmed this finding in a subset of 198 patients using a known biological indicator, or “biomarker”, of maternal smoking during pregnancy, in a gene called aryl-hydrocarbon receptor repressor (AHRR). In this proposed study, we aim to replicate the association between this biomarker of maternal pregnancy smoking and number of gene deletions in a larger group of 300 children with ALL. Our second aim is to confirm that tobacco smoke is causing the increased number of deletions in leukemia cells through errors in “RAG recombination”, which will require cutting edge DNA sequencing technology to investigate patterns of “RAG recombination” in the DNA located around the deletions found in leukemia cells. If we can provide evidence that tobacco smoke is associated with increased leukemia deletions due to “RAG recombination”, this will support that tobacco exposure during pregnancy may cause childhood ALL and will have a high impact on tobacco-related disease research. This is the first study to investigate how tobacco smoke may cause gene deletions in childhood ALL. Also, it is an unbiased study because it will use a known biomarker for tobacco exposure rather than relying on parent interview data. By confirming tobacco smoke exposure as a risk factor for childhood ALL, we may be able to prevent future cases of this disease.