The main areas of research activity for 1999 can be briefly summarized as follows:

The CCG remains a vital resource for epidemiological studies on childhood cancer. An important focus of current research is on the possible role of pesticides in the etiology of childhood cancer: studies that address this issue include separate case-control studies of AML and ALL, and a housedust sampling study that has assayed pesticide concentrations in the homes of children with ALL, and controls (Buckley). A new molecular epidemiological study has recently been funded to examine the role of pesticides in childhood non-Hodgkin's lymphoma (Buckley).

Other CCG related studies include a proposed case-control study of hepatoblastoma and factors associated with prematurity. (VanTornout and Buckley) and two studies being conducted out of the University of Minnesota (Julie Ross, P.I.) for which Dr. Buckley is a co-investigator (a case-control study of Downs syndrome/leukemia and an infant leukemia case/control study to examine the role of exposure to topoisomerase inhibitors).

Dr. Preston-Martin's main area of interest remains childhood brain tumors. She coordinated a highly ambitious multi-national case-control study of brain tumors, including 1218 cases and 2223 controls at 9 centers, and much of her energies in recent years has been focused on a complete and through analysis of the data from that study. Among the publications to come from the study have been manuscripts on maternal consumption of cured meats and vitamin supplements during pregnancy; exposure to tobacco smoke; use of electric blankets and water beds; and head injury. Additional publications will cover: epilepsy and anticonvulsant use; residential water source and nitrite/nitrate content of household water as assessed from dipstick measurements; medication use by mothers during the pregnancy and by the children; birth characteristics (including birthweight, parental age, birth order and history of birth defects in the index child or his siblings); use of rubber baby bottle nipples and pacifiers; child’s diet and other early exposures.

Interest in the role of genetic susceptibility has grown steadily over the last five years, and Dr. Van Tornout has established a very active program in this area. Current projects include studies of neuroblastoma, brain tumors, and Ewing’s sarcoma. Preliminary data indicate that GST polymorphisms may be associated with risk of neuroblastoma (GST-P1 null conferring high risk) and brain tumors (associations with GST-P1, GST-T1 and MTHFR). R01 applications are in development for both these tumors to investigate the role of genetic susceptibility. For brain tumors, the involvement of MTHFR raises the intriguing possibility of a gene-environment interaction between this key enzyme of folate metabolism and level of folate intake during pregnancy. Consultation with the Biostatistics Core was particularly vital in the design of this study, since the study needed to be able to address the potential role of the case’s genotype, the mother’s genotype, the case’s exposures and the mother’s exposures, as well as interactions.

In addition, Dr. Buckley has collaborated on a CCG study that showed clear evidence of interaction between and environmental exposure (induction chemotherapy, in AML patients, given either by standard or intensively timed) and a metabolic polymorphism (GST-P1) in determining a patient’s risk of experiencing a lethal toxicity.

Dr. Bhatia is conducting several studies on second malignancies for children with cancer. One group of particular interest is Hodgkin's disease survivors who have a very high risk of secondary breast cancer, and Dr. Bhatia is working through the international organization, SIOP, to assemble a cohort of Hodgkin's patients with SMN. She is also collaborating on a study that will identify mutations (germline/somatic) in candidate genes (p53, ATM, BRCA1) and establish a protocol for annual mammographic screening. Other SMN projects include a study on the role of genetic susceptibility in the development of secondary myelodysplasia, and studies of SMN following childhood ALL and bone marrow transplantation. Finally, she is collaborating with Dr. Buckley in developing a database of SMN patients in CCG, to identify cases, construct a pedigree, and correlate risk with socio-demographic, clinical and treatment characteristics.

Six pairs of identical twins have been studied in a pilot program to evaluate the use of twins in assessing long-term effects of treatment. For many outcome measures, such as cognitive function, reproductive effects, growth and development, etc, there are no simple ‘population norms’ that can be usefully applied. However, an unaffected, genetically identical twin provides a near-perfect control, giving accurate information on what would have been expected for these measures, had the child not been exposed to cancer therapy. In the pilot study, the six pairs were evaluated with a brain MRI, a CT scan of bone density, a cardiac evaluation, a respiratory evaluation, and complete physical examination and comprehensive health questionnaire and a panel of psycho-cognitive measurements.

Exposure assessment is particularly problematic for epidemiological studies of childhood cancer because of the wide geographic spread of study subjects and controls. The impracticality of direct exposure assessment has forced investigators to refine, as much as possible, the questionnaire tools at their disposal. Where direct measurement of environmental exposures have been possible, studies have been designed to capitalize on the opportunity. This applies to studies on EMF exposure (carried out in Los Angeles county by Dr. John Peters and others, and nationally by Dr. Linet, in collaboration with Dr. Robison and Dr. Buckley), radon exposure (in collaboration with NCI and NIEHS) and pesticide, PAH, metals and ETS exposure (through house dust sampling). The house dust study is particularly important, in that it required coordination of the efforts of USC investigators, with the subcontractors at U. Minnesota (responsible for case-control ascertainment and interviewing), at the NCI (responsible for establishment of the EMF cohort), at Westat (responsible for sample collection), and at SouthWest Research Institute and Chester Labnet (responsible for performing all assays). The end result was a unique data base that included extensive interview information and comprehensive analyses of contaminants of house dust in 550 homes. Five manuscripts are currently in preparation, reporting the results of analysis of these data, not only with respect to the key hypothesis that exposure to one or more components of house dust might increase leukemia risk, but also to give new insights into factors which correlate with high levels of contamination of the home with any of the analyzed materials.