Cancers adapt to their mutational load by buffering protein misfolding stress

In asexual populations that don’t undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging consequences of this mutational load is not well understood. Here, we investigate the functional consequences of mutational load in 10,295 human tumors by quantifying their phenotypic response through changes in gene expression. Using a generalized linear mixed model (GLMM), we find that high mutational load tumors up-regulate proteostasis machinery related to the mitigation and prevention of protein misfolding. We replicate these expression responses in cancer cell lines and show that the viability in high mutational load cancer cells is strongly dependent on complexes that degrade and refold proteins. This indicates that upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities. Statement of Significance Cancers can successfully survive an accumulation of thousands of protein-damaging mutations. Here, we show that high mutational load tumors mitigate these damaging consequences by up-regulating complexes that buffer against protein misfolding stress – providing novel therapeutic vulnerabilities and suggesting that disruption of proteostasis is a hallmark of somatic evolution.