Frequent mutations in acetylation and ubiquitination sites suggest novel driver mechanisms of cancer

Abstract

Background: Discovery of cancer drivers is a major goal of cancer research. Driver genes and pathways are often predicted using mutation frequency, assuming that statistically significant recurrence of specific somatic mutations across independent samples indicates their importance in cancer. However, many mutations, including known cancer drivers, are not observed at high frequency. Fortunately, abundant information is available about functional "active sites" in proteins that can be integrated with mutations to predict cancer driver genes, even based on low frequency mutations. Further, considering active site information predicts detailed biochemicalmechanisms impacted by the mutations. Post-translational modifications (PTMs) are active sites that areregulatory switches in proteins and pathways. We analyzed acetylation and ubiquitination, two important PTM types often involved in chromatin organization and protein degradation, to find proteins that are significantly affected by tumor somatic mutations.Methods: We performed computational analyses of acetylation and ubiquitination sites in a pan-cancer dataset of 3200 tumor samples from The Cancer Genome Atlas (TCGA). These analyses were targeted at different levels of biological organization including individual genes, pathway annotated gene sets, and protein-protein interaction networks.Results: Acetylation and ubiquitination site mutations are enriched in cancer with significantly stronger evolutionary conservation and accumulation in protein domains. Gene-focused analysis with the ActiveDriver method reveals significant co-occurrences of acetylation and ubiquitination PTMs and mutation hotspots in known oncoproteins (TP53, AKT1, IDH1) and highlights candidate cancer driver genes with PTM-related mechanisms (e.g. several histone proteins and the splicing factor SF3B1). Pathway analysis shows that PTM mutations in acetylation and ubiquitination sites accumulate in cancer-related processes such as cell cycle, apoptosis, chromatin regulation, and metabolism. Integrated mutation analysis of clinical information and protein interaction networks suggests that many PTM-specific mutations associate with decreased patient survival. Conclusions: Mutation analysis of acetylation and ubiquitination PTM sites reveals their importance in cancer. As PTM networks are increasingly mapped and related enzymes are often druggable, deeper investigation of specific associated mutations may lead to the discovery of treatment-relevant cellular mechanisms.