Department of Biology, Stanford University, Stanford, United States.
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, United States.
Elife. 2024 Nov 25;12:RP87301. doi: 10.7554/eLife.87301.
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 the upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities.
在不进行重组的无性繁殖种群中，如癌症，由于突变在全基因组范围内的连锁，有害突变很容易积累。尽管存在数千种有害突变的这种突变负荷，但许多肿瘤仍能茁壮成长。肿瘤如何在这种突变负荷的破坏性后果中存活下来还不是很清楚。在这里，我们通过量化基因表达的变化来研究 10295 个人类肿瘤中突变负荷的功能后果。使用广义线性混合模型 (GLMM)，我们发现高突变负荷肿瘤上调了与减轻和预防蛋白质错误折叠相关的蛋白质稳态机制。我们在癌细胞系中复制了这些表达反应，并表明高突变负荷癌细胞的活力强烈依赖于降解和重折叠蛋白质的复合物。这表明蛋白质稳态机制的上调对高突变负担肿瘤具有因果重要性，并揭示了新的治疗弱点。
