Childhood acute lymphocytic leukemia (ALL) is the most common pediatric cancer. The exact cause is not known in most individual cases, but past epidemiological research has suggested a number of potential environmental and genetic risk factors, including TEL-AML fusion gene, which can initiate childhood ALL in approximately 25% of subjects. However, this is usually insufficient and additional factor(s) are often required. The main hypothesis of this study is that the TEL-AML fusion gene in childhood B-cell ALL is induced by prenatal exposures of pregnant women to environmental risk factors, and by genetic polymorphisms in maternal genes that affect folate metabolism, such as methylenetetrahydrofolate reductase (MTHFR), and genes that prevent oxidative stress such as NAD(P)H quinone oxidoreductase (NQO1). A secondary hypothesis is that the postnatal events required for development of ALL are environmental factors such as exposure to second-hand tobacco smoke and/or pesticides exposure, genetic polymorphism in the child's NQO1 gene, and interaction between these factors.
Our specific aims are: (1) to evaluate the associations between presence or absence of TEL-AML1 fusion gene in ALL cases and maternal polymorphisms in NQO1 and MTHER genes and environmental exposures of mothers during the child prenatal period (case-case analysis), (2) to investigate the association between childhood ALL risk and the child's NQO1 genotype and postnatal environmental exposures, by comparing ALL cases to age-matched non-cancer control subjects (case-control), and (3) to compare ALL cases who have the fusion, ALL cases who do not have it , and the controls subjects with respect to their genotype and environmental exposure (Case-case-control).To carry out these aims, we are proposing a case-control study of 300 ALL subjects (less than 14 years old) and 300 control subjects and their respective mothers. Cases and controls will be matched on sex and age. Cases will be recruited from the National Cancer Institute of Cairo University, Egypt, and controls will be recruited from the Orthopedic Department of Cairo University Hospital. We will administer a standard questionnaire to mothers. We will draw 5-7 cc blood form the child, and we will also take few drops of blood on a blood spot card from the mothers. From the child's sample we will measure TEL-AML fusion genes by florescent in situ hybridization technique. Mutations in MTHFR and NQO1 genes will be tested by PCR using the specific primers. Given the high number of cases that can be recruited from one center in Egypt, the high potential for environmental exposures in Egypt, and our demonstrated ability to collect biological samples and to obtain high-quality data in our previous case-control study of childhood hematological malignancies, this application represents a unique opportunity to address important questions concerning risk factors for childhood ALL.

Public Health Relevance

This research plan addresses an interesting and important public health question. Knowledge of the genetic factors associated with Childhood Acute Lymphocytic Leukemia (ALL), as well as an understanding of environmental risk factors, will help public health officials to implement strategies for effective prevention of childhood leukemia and reduce the burden of ALL in Egypt. This proposal has also a great potential to provide information that wil be useful not only to Egypt but to the wider scientific community since information gained from this proposal could be applied to other parts of the world.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Special Emphasis Panel (ZCA1-SRRB-D (O1))
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Simonds, Naoko
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National Hepatology/Tropical Med Research Institute
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