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BACKGROUND: The developmental context in which genetic alterations occur is crucial to understand disease progression. In pediatric cancer, modeling tumor formation in the right cell type is necessary to faithfully recapitulate the unique nature of pediatric tumors. The Cre-LoxP system is a powerful tool to modulate gene expression in specific cell types at discrete developmental time windows.METHODS: We used Cre-LoxP mouse models to study the role of the oncofetal transcription factor in pediatric brain tumor formation. We characterized our model using histology, DNA methylation based copy number variant (CNV) analysis on fresh frozen and FFPE derived samples, RNA sequencing, whole genome sequencing and whole genome CRISPR Cas9 screening.RESULTS: We generated a new model for overexpressing brain tumors, but discovered an unexpected CNV at the locus by DNA methylation analysis. We confirmed the CNV via whole genome sequencing and found that it was likely mediated by Cre-recombination at the transgene insertion site. Both the tumor transcriptome and genetic dependencies are substantially shaped by this CNV.CONCLUSIONS: Our work demonstrates the necessity of copy-number analysis when working with transgenic Cre-LoxP mouse models. Assessing CNVs should become a standard evaluation procedure when reporting new tumor models, preventing misleading conclusions that could dramatically impact the reliability of preclinical studies.