Genetically regulated expression underlies cellular sensitivity to chemotherapy in diverse populations

Area of Science:

• Pharmacogenomics
• Cancer Biology
• Human Genetics

Background:

• Chemotherapeutic agents exhibit variable efficacy among cancer patients, highlighting the impact of genetic variation on drug response.
• Lymphoblastoid cell lines (LCLs) from diverse ancestral populations offer a valuable model for investigating genetic influences on drug cytotoxicity.

Purpose of the Study:

• To identify genetic loci and genes associated with chemotherapy-induced cytotoxicity across diverse ancestral populations.
• To understand the genetic basis of differential responses to cancer chemotherapeutic agents.

Main Methods:

• Utilized lymphoblastoid cell lines from three 1000 Genomes Project populations.
• Performed genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS) on drug response phenotypes (IC50, AUC).
• Conducted functional studies involving gene knockdown in a lung cancer cell line (A549).

Main Results:

• Identified four unique loci through GWAS and three genes through TWAS significantly associated with chemotherapy-induced cytotoxicity.
• Discovered that increased STARD5 predicted expression correlated with decreased etoposide half-maximal inhibitory concentration (IC50).
• Demonstrated that STARD5 knockdown in A549 cells led to decreased sensitivity to etoposide.

Conclusions:

• Genetic factors significantly contribute to variations in chemotherapy drug response.
• STARD5 is implicated as a gene influencing sensitivity to etoposide.
• Findings advance the understanding of pharmacogenomics for personalized cancer treatment development.