Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin

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 alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues 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 downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes 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 transcriptional and translational changes, shedding light on the tumor’s epigenetic landscape and the role of its cell-of-origin. [Display omitted] •Pan-cancer epigenetic aberrations and their transcriptional and translational changes•FGFR2 and EGFR hypomethylation are bona fide driver DNA methylation events•STAT5A methylation is a potential switch for immunosuppression in squamous tumors•Methylation subtypes illuminate cell origin, tumor heterogeneity, and tumor phenotype Liang et al. catalog pan-cancer DNA methylation with concordant transcriptional and translational changes, revealing lineage-specific epigenetic driver FGFR2 hypomethylation in uterine corpus endometrial carcinoma, and STAT5 hypermethylation as an immunosuppression switch in squamous tumors. They also identify methylation-driven subtypes associated with cell-of-origin, tumor heterogeneity, tumor phenotype, and links to therapeutic potential.