# Towards Personalized Chemotherapy in Gastrointestinal Cancers: Prospective Analysis of Pharmacogenetic Variants in a Russian Cohort

## TL;DR

This study examines genetic variations in Russian patients with gastrointestinal cancers to better understand how these variations affect chemotherapy outcomes and side effects.

## Contribution

The study provides the first comprehensive pharmacogenetic profile of a Russian cohort for gastrointestinal cancer chemotherapy.

## Key findings

- DPYD rs2297595 and UGT1A1 rs8175347 variants were more frequent in the Russian cohort compared to European populations.
- CYP2C8 rs10509681 frequencies were similar to European populations and linked to taxane-induced neuropathy risks.
- Variants in GSTP1, ERCC1, CDA, SLC31A1, MTHFR, and TYMS showed associations with chemotherapy efficacy and toxicity.

## Abstract

Background/Objectives: Pharmacogenetic variability plays a crucial role in determining both the efficacy and toxicity of chemotherapy for gastrointestinal cancers. However, data on allele frequencies and their clinical relevance in Russian populations remain scarce. Methods: We conducted a prospective observational study of 412 patients with gastrointestinal malignancies between 2020 and 2023. Pharmacogenetic testing was performed prior to the initiation of chemotherapy using real-time allele-specific PCR and microarray hybridization technology. Polymorphisms in the DPYD, UGT1A1, CYP2C8, CYP3A5, GSTP1, ERCC1, XPC, CDA, MTHFR, TYMS, and SLC31A1 genes were analyzed. Results: The frequency of most variants was consistent with those reported in European populations, reflecting the ethnic proximity of the studied cohort. Several clinically relevant variants were identified: DPYD rs2297595 occurred more frequently than in European cohorts, and UGT1A1 rs8175347 was observed at a higher prevalence, underscoring the potential risk of irinotecan-related neutropenia and diarrhea. CYP2C8 rs10509681 was present at frequencies comparable to European populations and is associated with an increased risk of taxane-induced peripheral neuropathy. Other markers (GSTP1, ERCC1, CDA, SLC31A1, MTHFR, TYMS) demonstrated variable associations with chemotherapy efficacy and toxicity, consistent with findings from previous international studies. Conclusions: This study provides the first comprehensive description of pharmacogenetic polymorphisms in a Russian cohort of patients with gastrointestinal cancers. Our findings confirm the clinical importance of DPYD and UGT1A1 testing and highlight additional variants of potential interest.