Proteogenomic view of cancer epigenetics: the impact of DNA methylation on the cancer proteome

Abstract Aberrant DNA methylation disrupts normal gene expression in cancer and broadly contributes to oncogenesis. We previously developed MethylMix, a model-based algorithmic approach to identify epigenetically regulated driver genes. MethylMix identifies genes where methylation likely executes a functional role by using transcriptomic data to select only methylation events that can be linked to changes in gene expression. However, given that proteins more closely link genotype to phenotype recent high-throughput proteomic data provides an opportunity to more accurately identify functionally relevant abnormal methylation events. Here we present ProteoMix, which refines nominations for epigenetic driver genes by leveraging quantitative high-throughput proteomic data to select only genes where DNA methylation is predictive of protein abundance. Applying our algorithm across three cancer cohorts we find that ProteoMix narrows candidate nominations, where the effect of DNA methylation is often buffered at the protein level. Next, we find that ProteoMix genes are enriched for biological processes involved in cancer including functions involved in epithelial and mesenchymal transition. ProteoMix results are also enriched for tumor markers which are predictive of clinical features like tumor stage and we find clustering on ProteoMix genes captures cancer subtypes.