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 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.

Automated summary

DNA methylation is critical for maintaining cellular identity, but is often dysregulated in tumors. This study identified aberrant methylation in different cancer types and its association with changes in RNA and protein abundance. Lineage-specific epigenetic drivers and the role of methylation subtypes in tumor heterogeneity and phenotypes were also revealed.