Genetic inheritance clearly can influence the risk of developing childhood cancer. Down's syndrome children have a 100-fold increased risk of leukemia. Ewing's sarcoma is virtually unknown in African-Americans. Lymphoma occurs 70 times more frequently in individuals with ataxia telangiectasia than in the general population. Some progress has been made in pinpointing genetic causes of childhood cancer - identification of the retinoblastoma (Rb) gene and recognition that mutations in the p53 gene give rise to the Li-Fraumeni family cancer syndrome - and there is increasing evidence that polymorphisms in metabolic enzymes play a role in determining cancer risk and response to therapy.

A major interest of the Childhood Cancer Research Core is in identifying the origins of genetic susceptibility and using these data to better understand the role of environmental factors. As mentioned above it is very difficult, using traditional epidemiological approaches, to firmly establish a causative role for a given environmental factor because of inevitable uncertainties about exposure levels (and potential biases). However, evidence for a gene-environment interaction of a given environmental exposure with a host susceptibility locus would provide powerful confirmatory evidence implicating the environmental factor.

Studies related to genetic susceptibility to childhood cancer which Childhood Cancer Core members have either conducted or contributed significantly to over the last five years are listed on the top.

Project A: Genetic Epidemiology of Colorectal Cancer in the Young

Pedigrees have been constructed on patients with colon cancer diagnosed before 21 years of age, and the risk of cancer in family members computed.

Project B: CCG Genetics Registry

In 1990, CCG activated a protocol for the registration of patients that have characteristics suggesting a genetic or familial basis for their disease to collect information on a population of pediatric cancer patients with congenital abnormalities, genetic and familial conditions which demonstrate cancer susceptibility, second malignancy, childhood cancer in first degree relatives and twins with cancer. Pedigrees have been constructed for over 1100 families, and a comparison of observed patterns of cancers with expected numbers, has been carried out for probands with ALL.

Project A: Role of Genetic Susceptibility in the Development of Secondary Myelodysplasia

Secondary myelodysplasia occurs in some patients following therapy with alkylating agents and in patients undergoing autologous transplants for lymphoma. This study will examine genetic polymorphisms for drug metabolism to determine whether genetic susceptibility potentially plays a role in the development of MDS in some patients. Genomic instability will be assessed by the presence of microsatellite instability, an increased mutation frequency (GPA gene/HPRT), telomere shortening or altered activity, and acquisition of cytogenetic abnormalities.

Dr. Preston-Martin is a consultant for two molecular genetic studies of pediatric brain neoplasms. The first (conducted by collaborators in the West Coast Childhood Brain Tumor study) detected ras mutations, to evaluate their potential use as biomarkers of chemical exposure.

The second project relates to p53 mutations in Los Angeles children with primary brain tumors. This project is headed by Dr. Roberta McKean-Cowdin, a postdoctoral fellow working with Dr. Preston-Martin. She has received pilot funding from the SCEHSC.

Dr. Van Tornout has demonstrated an association of polymorphisms in GST-P1 and the development of brain tumors in children. A grant application has been submitted to pursue this research.

Finally, Dr. Preston-Martin is collaborating with Dr. Little, from the University of Aberbeen, in a proposed study of metabolic enzyme polymorphisms (including MTHFR, FOLR1, NAT1, CYC1A1, GST-T1, GST-M1 and GST-M3) using stored neonatal spot bloods and data from the West Coast Consortium, to look for genetic susceptibility alleles and test for GxE interaction of these alleles and exposures such as ETS exposure and parental occupational exposures.

Project C: Genetic Epidemiology of Ewing's Sarcoma in Children

Dr. Jan Tornout is funded to examine steroid receptor genes in children with Ewing's sarcoma, and in a parental control group. The ultimate goal of this research is to find an explanation for the dramatic race-specific incidence pattern of Ewing's, which is virtually never reported in African-Americans.

Project D: Polymorphic Metabolizing Genes and the Biology of Neuroblastoma

Pilot data have shown an increase in risk of neuroblastoma associated with homozygosity for the null form of GST-P1. Other metabolic enzyme genes are currently being looked at, and a case-case study that will take advantage of an existing, comprehensive data base of epidemiological information from a previous CCG study is under development.

Project E: Influence of GST Polymorphisms on Risk of AML in Children and on Response to Therapy

This is a collaborative study, conducted out of the University of Minnesota (Dr. Stella Davies, P.I.) to study genetic polymorphisms in the etiology and as determinants of response to therapy in children with AML. Dr. Buckley is providing statistical support for analyses that involve clinical data.