| In the United States, Ewing's sarcoma is the second most common bone tumor after osteosarcoma, affecting mostly adolescents and young adults. Worldwide there is a well-established difference in incidence of this disease geographically and ethnically and in some populations there is a virtual absence of this cancer. Lack of a change in incidence as a given population moves to a different geographic location has long suggested involvement of a genetic factor(s). Although much is known about the molecular genetics of this disease, the responsible genetic factor(s) have not been identified.;Ewing's sarcoma family of tumors is characterized by a reciprocal translocation between the EWS gene and members of the ets-transcription factor family of genes. In ninety eight percent of Ewing's sarcoma cases there is evidence of such a translocation. Additional sites of genetic control include the insulin-like growth factor-I (IGF-I) and nerve growth factor (NGF) pathways. IGF-I is part of the growth hormone (GH)/IGF-I axis that is upregulated during puberty, a time when the incidence of Ewing's sarcoma peaks. IGF-I and its downstream pathway are involved in the tumor biology of Ewing's sarcoma. Vitamin D induced expression of NGF by osteoblasts may account for the predilection of Ewing's sarcoma to bone tissue and this pathway may be related to disease etiology.;We hypothesize that the genetic factor(s) responsible for the ethnic specific incidence of Ewing's sarcoma may be involved in the translocation event, the insulin-like growth factor pathway, and/or the nerve growth factor pathway. In order to test our hypothesis, we enrolled 97 cases with Ewing's sarcoma identified through Childrens Hospital Los Angeles, the California Cancer Registry, and via a study internet site along with both their parents and siblings as ethnically matched controls. Analysis was carried out using the Family Based Association Test (FBAT) program which utilizes the entire family structure in order to determine if any association exists between the disease and a maker. We found a significant association between Ewing's sarcoma a single nucleotide polymorphism located upstream of the EWS gene (p = 0.003, recessive model) and the IRS gene (134 by allele, p = 0.016, recessive model). |
