Aneuploidy tolerance caused by BRG1 loss allows chromosome gains and recovery of fitness

Aneuploidy results in decreased cellular fitness in many species and model systems. However, aneuploidy is commonly found in cancer cells and often correlates with aggressive growth, suggesting that the impact of aneuploidy on cellular fitness is context dependent. The BRG1 (SMARCA4) subunit of the SWI/SNF chromatin remodelling complex is frequently lost in cancer. Here, the authors show that BRG1 loss can lead to changes that allow tolerance to aneuploidy. This creates a setting where karyotype changes can be explored without a fitness penalty, allowing adaptation to changing environments. This could play an important role in the progression of BRG1 deficient cancers. Aneuploidy results in decreased cellular fitness in many species and model systems. However, aneuploidy is commonly found in cancer cells and often correlates with aggressive growth, suggesting that the impact of aneuploidy on cellular fitness is context dependent. The BRG1 (SMARCA4) subunit of the SWI/SNF chromatin remodelling complex is frequently lost in cancer. Here, we use a chromosomally stable cell line to test the effect of BRG1 loss on the evolution of aneuploidy. BRG1 deletion leads to an initial loss of fitness in this cell line that improves over time. Notably, we find increased tolerance to aneuploidy immediately upon loss of BRG1, and the fitness recovery over time correlates with chromosome gain. These data show that BRG1 loss creates an environment where karyotype changes can be explored without a fitness penalty. At least in some genetic backgrounds, therefore, BRG1 loss can affect the progression of tumourigenesis through tolerance of aneuploidy.

Automated summary

Aneuploidy causes a decrease in cellular fitness, but it is commonly found in cancer cells and often associated with aggressive growth, indicating that the impact of aneuploidy on cellular fitness depends on the context. In this study, the loss of the BRG1 subunit of the SWI/SNF chromatin remodeling complex is shown to enable tolerance to aneuploidy. This creates an environment where chromosomal changes can occur without a fitness penalty, allowing adaptation to changing environments. This may play a significant role in the progression of BRG1-deficient cancers.