In-utero smoke exposure and epigenetic activation of GFI1-family oncogenes

Medulloblastoma is the most common brain cancer in children, with fewer than 65% of patients surviving to adulthood. Although survival has improved in recent decades with more targeted and aggressive therapy, disease prevention remains the ultimate goal of pediatric cancer research. In order to prevent medulloblastoma occurrence, we must first identify modifiable causes of the disease. One cause of medulloblastoma is increased activity of a gene called GFI1. We recently demonstrated that in-utero exposure to tobacco smoke causes changes in this gene among newborn children, potentially leading to its activation. This suggests that eliminating tobacco smoke exposure in pregnant women could help to reduce the occurrence of this aggressive childhood brain cancer. Although this is exciting early evidence, we need to perform a more detailed investigation in a larger population of children, both with and without medulloblastoma, to make firmer conclusions Our lab has access to blood specimens, taken at birth, from approximately one thousand children who went on to develop medulloblastoma. We also have newborn blood specimens from thousands of healthy children with which to make comparisons. We propose to investigate specific changes to the DNA of 260 children who developed medulloblastoma and 466 cancer-free children in order to determine if smoking-associated DNA changes are more common in the children who developed brain cancer. We believe that the proposed study will have a meaningful and lasting impact on tobacco-related disease research due to its value in three key areas. First, the project has the potential to identify a modifiable cause of childhood brain cancer, potentially helping us to prevent future occurrences. Second, successfully linking specific DNA changes associated with in-utero smoke exposure to future cancer development in children will open the door to many future studies of diverse tobacco-associated pediatric illnesses. Finally, linking maternal smoking during pregnancy to risk of cancer in her children could help motivate young women to give up tobacco products for the sake of their child’s health.