Using Saccharomyces cerevisiae as a tool for mapping genetic variants underlying differences in response to anti-cancer agents

There are variations in response to anti-cancer agents amongst individuals because they are complex traits controlled by multiple genes and environmental factors. Here, we aimed to decipher the genes controlling the variations in response to aspirin, metformin, disulfiram and 5-fluorouracil using quantitative trait loci (QTL) mapping in yeast before translating findings to humans. This approach was feasible due to the conservation of genes between these two organisms.

A panel of 111 F12 meiotic segregants generated from a four-parent S. cerevisiae cross were genotyped by whole genome sequencing. Segregants growth in different treatments were phenotyped using PHENOS. Subsequently, linkage-based fine QTL mapping was performed to locate regions of the genome and the identification of causative genes.

Linkage analysis has mapped hundreds of genetic loci in the yeast genome responsible for the variations in response to the agents tested. Conserved homologs to human genes were identified. Some hits have been previously supported in the literature such as the effect of aspirin and metformin on MTOR thus validating this screening approach. Novel genes identified and pathway enrichment revealed mechanisms by which these agents may exhibit their anti-cancer properties.

Detection of genetic variants influencing the differences in drug response could help identify individuals at risk or benefit of using anti-cancer agents. Current work includes validating the alleles of causative genes (Rad57 and VMA22) in yeast by reciprocal hemizygosity and allele swapping. This study could aid the development of biomarkers for drug response and validate the repurposing of drugs for cancer prevention.