Transient depletion of Polycomb group (PcG) proteins induces epigenetic cancer. This study shows that a temporary disruption of PcG-mediated transcriptional silencing in Drosophila leads to an irreversible switch to a cancer cell fate. This is linked to the derepression of genes that drive tumorigenesis, including members of the JAK-STAT pathway and zfh1, a fly homologue of the ZEB1 oncogene. These findings suggest that tumours can emerge through epigenetic dysregulation, leading to the inheritance of altered cell fates. The study demonstrates that reversible depletion of PcG proteins can induce cancer in the absence of driver mutations, indicating that epigenetic changes can drive tumorigenesis. The research highlights the role of PcG proteins in maintaining cellular memory and their involvement in developmental processes. The study also shows that the JAK-STAT pathway is activated in these epigenetically initiated cancers (EICs), and that the transcriptional repressor ZFH1 plays a key role in maintaining the tumour state. The results indicate that EICs are driven by a restricted set of irreversibly upregulated genes, including major members of the JAK-STAT pathway, rather than by the widespread dysregulation of cancer genes. The study further shows that EICs are autonomous immortal tumours that can metastasize and persist even after the restoration of normal PcG protein levels. The findings suggest that epigenetic events may play a major role in the early stages of oncogenesis or during tumour progression in some mammalian cancers. The study provides insights into the mechanisms underlying tumorigenesis and highlights the importance of epigenetic regulation in cancer development.Transient depletion of Polycomb group (PcG) proteins induces epigenetic cancer. This study shows that a temporary disruption of PcG-mediated transcriptional silencing in Drosophila leads to an irreversible switch to a cancer cell fate. This is linked to the derepression of genes that drive tumorigenesis, including members of the JAK-STAT pathway and zfh1, a fly homologue of the ZEB1 oncogene. These findings suggest that tumours can emerge through epigenetic dysregulation, leading to the inheritance of altered cell fates. The study demonstrates that reversible depletion of PcG proteins can induce cancer in the absence of driver mutations, indicating that epigenetic changes can drive tumorigenesis. The research highlights the role of PcG proteins in maintaining cellular memory and their involvement in developmental processes. The study also shows that the JAK-STAT pathway is activated in these epigenetically initiated cancers (EICs), and that the transcriptional repressor ZFH1 plays a key role in maintaining the tumour state. The results indicate that EICs are driven by a restricted set of irreversibly upregulated genes, including major members of the JAK-STAT pathway, rather than by the widespread dysregulation of cancer genes. The study further shows that EICs are autonomous immortal tumours that can metastasize and persist even after the restoration of normal PcG protein levels. The findings suggest that epigenetic events may play a major role in the early stages of oncogenesis or during tumour progression in some mammalian cancers. The study provides insights into the mechanisms underlying tumorigenesis and highlights the importance of epigenetic regulation in cancer development.