Genetic Susceptibility Factors in the Etiology of Neuroblastoma

DESCRIPTION: Neuroblastoma (NB) is a tumor of the peripheral nervous system. It is a neural crest cell derivative, originating from the sympathoadreanal lineage, and its development is related to that of normal sympathetic neurons. It is the most common malignancy of infancy. The early age at diagnosis distribution of NB suggests that events occurring in the preconceptional and prenatal periods may have an important role in the pathogenesis of this disease. Several epidemiologic studies have reported that maternal use of vitamins during pregnancy reduces the risk of NB. The embryonic origins and biology of NB provide further evidence for an etiologic role for vitamins. We propose to conduct a national case-parent triad study including approximately 1,041 NB cases under the age of 5 years at diagnosis to evaluate the independent association of common genetic polymorphisms involved in folate, vitamin A, and related metabolic and transport pathways with the risk of NB. We will examine the risk associated with 29 genes (727 SNPs). We will take a comprehensive approach to select coding and noncoding and haplotype-tagging SNPs. We will also evaluate the joint effects of multiple genes on the risk of NB and the effects of gene-exposure interactions on the risk of NB. Folate, vitamin A, and choline intake will be of primary interest. Finally, we will evaluate genetic effects within NB subgroups defined by age at diagnosis and a classification schema based on age, MYCN oncogene status, histology, and DNA ploidy. We propose to enroll cases and their parents diagnosed over a three-year period. Cases will be identified via the Childhood Cancer Research Network, a North American childhood cancer registry system directed by the Children's Oncology Group. The study will involve DNA collection from the mother, father, and index child with NB. Dietary and supplemental vitamin intake during pregnancy will be obtained from the mother using a validated questionnaire using additional probes to differentiate the mother's usual diet from dietary habit changes during pregnancy. For deceased cases, DNA will be available via the COG Neuroblastoma Biology Protocol DNA bank. Neuroblastoma has a unique age-incidence and biology that may provide insight into the in utero origins of childhood cancer. Previous epidemiologic and biology studies have suggested the role for vitamin intake in the prevention of NB. No previous study has included this many cases and extensively investigated the role of genetic susceptibility in neuroblastoma. The investigation of vitamins and associated genetic factors will provide important clues to the etiology and potential prevention of this cancer. PUBLIC HEALTH RELEVANCE: Cancer is an important cause of death in children, and increasingly linked with late disease- and treatment-related morbidity. Neuroblastoma has a unique age-incidence and biology that may provide clues to the in utero origins of childhood cancer. Insight into the vitamin pathways that may prevent neuroblastoma is offered by our study of genes and gene-exposure interactions. This approach will significantly help establish whether vitamin associations are causal. The determination of preventive factors for neuroblastoma is also broadly relevant as vitamins have been associated with a reduced risk of other childhood cancers.