We have used the rat tyrosine hydroxylase promotor to overexpress MYCN in the neural crest of transgenic mice, resulting in a mouse model for neuroblastoma. Using PCR analysis of microsatellite markers, we conducted a genome-wide analysis in tumors from these animals. Regions of chromosomes 1, 3, 10, 11, 14, and 18 were affected in 20-50% of tumors. Analysis of a subset of these tumors by comparative genomic hybridization was consistent with the microsatellite data. The changes on mouse chromosomes 1, 11, 14, and 18 were syntenic with corresponding regions of loss of heterozygosity in human neuroblastoma, suggesting that genes implicated in the mouse tumors may also play a role in the pathogenesis of the human disease. One-third of the mouse tumors shared abnormalities on chromosomes 1, 3, and 10, whereas the remainder of tumors did not show this combination. These data suggest that genetic mutations on chromosomes 1, 3, and 10 cooperate in the pathogenesis of neuroblastoma and that neuroblastoma in the mouse arises from at least two distinct genetic pathways, one of which is dependent on lesions in chromosomes 1, 3, and 10, the other of which is not.