Population-Specific Pharmacogenetic Variants Associated with Chemotherapy Response in the Bulgarian Population

Background/Objectives: Pharmacogenetic variability influences the efficacy and toxicity of anticancer therapies. However, Eastern European populations remain underrepresented in pharmacogenetic databases. This study aimed to characterize pharmacogenetic variants relevant to chemotherapy response in the Bulgarian population and compare their allele frequencies with reference populations. Methods: Ninety individuals were included, comprising 50 patients with colorectal, non-small cell lung, or breast cancer and 40 healthy controls. Genomic DNA and circulating cell-free DNA were analyzed by next-generation sequencing targeting pharmacogenetic genes involved in drug metabolism, transport, and DNA repair. Allele frequencies were compared with gnomAD v2.1.1 reference data. Sensitivity analyses compared Bulgarian controls with Bulgarian non-cancer and combined Southern European, Northwestern European, and Other non-Finnish European non-cancer populations. Results: Twenty-three pharmacogenetic variants were evaluated. Six variants remained statistically significant after Benjamini–Hochberg correction in both Fisher’s exact test and the two-proportion Z-test. Five variants—DPYD c.2194G>A, XPC c.2815C>A, EGFR c.1562G>A, XRCC1 c.1196A>G, and ERCC2 c.2251A>C—showed higher allele frequencies, whereas ERCC2 c.934G>A was less frequent in the Bulgarian cohort. DPYD c.85T>C remained significant after correction in the Z-test but not in Fisher’s exact test. Sensitivity analyses confirmed the significance of XPC c.2815C>A in both reference-population comparisons, while DPYD c.85T>C remained significant only against the combined European reference population. Conclusions: Several pharmacogenetic variants showed distinct allele frequencies in the Bulgarian cohort. XPC c.2815C>A demonstrated the most robust population-specific pattern across sensitivity analyses. These findings highlight the value of locally derived pharmacogenetic data for precision oncology and pharmacogenetically guided treatment strategies.