Cancer Cell

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alter-ations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tis-sues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregula-tion and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression consti-tutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcrip-tional and translational changes, shedding light on the tumor's epigenetic landscape and the role of its cell-of-origin.