The Genetic Basis of Variation in Response to Chemotherapy and Cancer Chemoprevention Drugs in Saccharomyces cerevisiae

There is an inter-individual variation in drug response to anti-cancer agents because it is a complex trait controlled by multiple genes and environmental factors. This thesis explores the genes controlling variation in response to chemotherapy drugs 5-fluorouracil and oxaliplatin as well as cancer chemoprevention agents aspirin, salicylic acid, metformin, disulfiram with copper and curcumin by using quantitative trait loci (QTL) mapping in a model organism Saccharomyces cerevisiae that could potentially identify targets for future human studies. This approach was feasible due to the conservation of genes between these two organisms. A panel of 111 F₁₂ meiotic recombinant segregants from a four-parent S. cerevisiae advanced intercross lines cross previously generated and genotyped by whole genome sequencing was used. Segregant growth under different drug treatments was measured using PHENOS. Subsequently, linkage-based fine QTL mapping was performed to locate associated regions of the genome and identify causative genes. In this study, linkage analysis has mapped hundreds of genetic loci in the yeast genome responsible for the variation in response to the agents tested. Conserved homologs to human genes were identified. Some associated hits are supported by previously reported studies such as the effect of aspirin and metformin on TOR1 (mTOR in humans) and 5-fluorouracil on CDC21 (TYMS in humans) thus validating this screening approach. Identified genes and pathway enrichment revealed mechanisms by which these agents may exhibit their anti-cancer properties. Candidate genes were selected and functionally validated by reciprocal hemizygosity. Furthermore, the yeast gene deletion library was screened to discover additional pathways of aspirin’s response. Detection of genetic variants influencing the differences in drug response could help identify individuals at risk or benefit of using anti-cancer agents. This study could aid the development of biomarkers for drug response, identify targets for genetic testing and validate the repurposing of drugs for cancer prevention.