This project will use UK Biobank data to conduct an in-silico retrospective cohort study of the prevalence of severe toxic side effects associated with 5-Fluorouracil (5-FU) treatment in patients with esophageal, gastric, colorectal, breast, pancreatic, and head and neck cancers. 5-FU is a common chemotherapy drug with a narrow therapeutic index, and variations in the DPYD gene can lead to partial or complete dihydropyrimidine dehydrogenase (DPD) deficiency, resulting in severe toxicities. However, DPYD genotyping is not routinely performed in many healthcare systems, leaving some patients at high risk for preventable adverse effects.
Research questions include:
1. What is the prevalence of severe 5-FU-related toxicities in UK Biobank participants with these cancers?
2. What DPYD variants are present in this population?
3. Are specific demographic factors (age, sex, ancestry) associated with increased risk of severe toxicity?
The objectives are to:
* Identify common and rare DPYD variants using UK Biobank’s genotyping and exome sequencing data.
* Assess correlations between DPYD status and documented severe 5-FU side effects in linked health records.
* Analyze demographic and clinical covariates that may modify toxicity risk.
The rationale is that using the UK Biobank’s large-scale genomic and clinical dataset enables powerful detection of genotype-phenotype associations, including rare variants that might be missed in smaller studies. Findings could help refine pharmacogenomic guidelines and support broader adoption of DPYD testing to personalize 5-FU dosing, reduce severe toxicities, and improve patient safety in diverse populations.