Serial analysis of gene expression (SAGE) was used to identify genes that might be involved in the development or growth of medulloblastoma, a childhood brain tumor. Sequence tags from medulloblastoma (10229) and fetal brain (10692) were determined. The distributions of sequence tags in each population were compared, and for each sequence tag, pairwise chi2 test statistics were calculated. Northern blot was used to confirm some of the results obtained by SAGE. For 16 tags, the chi2 test statistic was associated with a P value < 10(-4). Among those transcripts with a higher expression in medulloblastoma were the genes for ZIC1 protein and the OTX2 gene, both of which are expressed in the cerebellar germinal layers. The high expression of these two genes strongly supports the hypothesis that medulloblastoma arises from the germinal layer of the cerebellum. This analysis shows that SAGE can be used as a rapid differential screening procedure.