How Genetic Variation Affects Childhood Cancer
How does normal human variation affect who will get childhood leukemia—and how they will respond to treatment? What role does environmental exposure play? And what does the future hold for those who survive childhood cancer?
At Cincinnati Children's Hospital Medical Center a team headed by Stella Davies, MBBS, PhD, MRCP, of the Division of Experimental Hematology, is conducting the most comprehensive research to date analyzing genetic variation and childhood leukemia. DNA from nearly 5,000 children from pediatric oncology centers throughout the United States is being analyzed.
Thirty years ago, only 5 to 10 percent of childhood cancers were cured. Today, the cure rate is 70 percent—but researchers want to learn what's different about the 30 percent of children whose cancer recurs, often leading to death. Dr. Davies and her colleagues are studying a battery of genes to identify those that affect whether treatment will be curative.
Because individuals metabolize chemotherapy drugs differently, the researchers are seeking predictors of drug success or failure so they can tailor a child's treatment. For instance, acute myeloid leukemia has a 50 percent cure rate—but 10 percent of children will die from side effects of the treatment itself. Previously, Dr. Davies has identified a gene called GSTT1 that predicts whether children with leukemia will get severe side effects from chemotherapy. Twenty percent of children do not have the GSTT1 gene, and in these children the risk of dying of complications of leukemia therapy is almost doubled.
In recent years, chemotherapy dose intensification has led to more cancer cures. But because chemotherapy drugs kill cancer cells by damaging DNA, they can also damage blood cells and cause leukemia, even though the original cancer is cured. While this is infrequent, it is deeply distressing for children and their families. Dr. Davies' laboratory is studying a group of children nationwide receiving some of the most dose-intensive chemotherapy treatments. The researchers hope to identify markers that will indicate the children at greatest risk of developing leukemia as a second malignancy, and to find early, reversible changes in the process.
If children survive cancer, what does the future hold for their health? This is a vital question for the 250,000 cancer survivors under age 30 in the United States today. Dr Davies' laboratory is the biological repository for a cohort study of almost 15,000 childhood cancer survivors being coordinated by investigators at the University of Minnesota. The laboratory has collected DNA samples on over 7,000 cohort members. Studies are looking at the genetic influences on the risk of cardiac side effects from treatment, the risk of obesity in leukemia survivors and the risk of second cancers in children treated with radiation therapy.
For further information regarding the Genotoxicity program, please contact Dr. Stella Davies at 513-636-1371. For additional information about the Division of Experimental Hematology, please contact Dr. David Williams at 513-636-0364. The Division of Experimental Hematology can be found in Room 6529 of Location R (Research Foundation Building).
