The dysregulation score method identifies epigenetic regulator genes that predict cancer prognosis and efficiency of cancer immunotherapy.

Epigenetic mechanisms play a crucial role in gene expression regulation during the initiation and progression of cancer. Despite this, over 600 epigenetic regulator (ER) genes, which are responsible for the reading, writing, and erasing of histone and DNA modifications, remain insufficiently characterized in the context of human cancer. In this study, we identified 272 cancer-specific ER genes that were dysregulated in cancer, as determined using a proposed dysregulation score method, based on analysis of over 19,000 paired tumor-normal human samples. Four novel dysregulated ER genes (DEGs), uniquely identified through this method, were shown to have roles in cell proliferation and invasion in melanoma cells. We proposed that loss-of-functional mutations within epigenetic domains may influence the dysregulation of ER genes. Signature scores derived from these DEGs can serve as convenient indicators of patient prognosis in different cancer types. Our findings demonstrated that DEGs in conjunction with immune checkpoints further enhance the prediction performance of the efficiency of cancer immunotherapy compared to using immune checkpoints alone, based on independent cancer cohorts. The DEG list is a valuable resource for translational cancer research, with implications for precision oncology and the development of more effective, individualized epigenetic medicines and therapy.