Pharmacogenetic Profiling of Genes Associated with Outcomes of Chemotherapy in Omani Healthy Controls.

Background/objectives: Pharmacogenomic screening plays a crucial role in optimizing chemotherapy outcomes and minimizing toxicity. Characterizing the baseline distribution of genetic variants in specific populations is essential to inform the prioritization of drug-gene combinations for clinical implementation. The objective of this study was to investigate the distribution of pharmacogenetic variants in 36 genes related to the fluoropyrimidine (FP) pathway among healthy Omani individuals, forming a foundation for future studies in cancer patients receiving FP-based chemotherapy.

Methods: Ninety-eight healthy Omani participants aged ≥18 years were recruited at the Sultan Qaboos Comprehensive Cancer Care and Research Center. Whole-blood samples were collected, and genomic DNA was extracted. Targeted next-generation sequencing was performed using a custom Ion AmpliSeq panel covering coding exons and splice-site regions of 36 genes involved in FP metabolism and response.

Results: A total of 999 variants were detected across the 36 genes, with 63.3% being heterozygous. The gene had the highest mutation frequency (76 mutations), while and had the lowest (<10 mutations). In , four functionally significant variants were found at frequencies ranging from 1 to 8.2% of the population. Missense mutations were also observed in and . Three actionable variants in and , associated with 5-fluorouracil and/or capecitabine response, were identified. Additionally, 27 novel single-nucleotide polymorphisms of unknown clinical significance were detected.

Conclusions: This study reveals key pharmacogenetic variants in the Omani population, underscoring the importance of integrating pharmacogenomic testing into routine care to support safer, more personalized chemotherapy in the region.